Methods for assessing risk of developing a viral disease using a genetic test

ABSTRACT

This document provides methods and materials related to treating a disease. For example, this document provides methods for treating a subject&#39;s disease based on identifying the risk of progressive multifocal leukoencephalopathy PML using a genetic test.

CROSS REFERENCE

This application is a divisional of U.S. application Ser. No.17/161,171, filed Jan. 28, 2021, which is a divisional of U.S.application Ser. No. 16/602,348, filed Aug. 15, 2019, now U.S. Pat. No.10,961,585, issued Mar. 30, 2021, which is a continuation of PCTApplication No. PCT/US2019/45721, filed Aug. 8, 2019, which claims thebenefit of U.S. Provisional Application No. 62/716,072, filed Aug. 8,2018, and U.S. Provisional Application No. 62/716,183, filed Aug. 8,2018, each of which is hereby incorporated by reference in its entirety.

REFERENCE TO A SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in XML format and is hereby incorporated byreference in its entirety. Said XML copy, created on Mar. 15, 2023, isnamed 56969_701_402_SL.xml and is 121,134,382 bytes in size.

BACKGROUND OF THE DISCLOSURE

Progressive multifocal leukoencephalopathy (PML) is a rare andpotentially fatal opportunistic infection of the central nervous systemthat is caused by a ubiquitous polyomavirus, the JC virus (JCV). WhileJCV is present at very high rates in the general population, PML remainsa rare disorder, albeit an important one because of the poor survivaland the severe neurological sequelae, and the recently demonstratedassociation with a variety of useful therapies, for example, natalizumabin multiple sclerosis (MS). A number of risk factors for PML have beendescribed but these are better viewed as necessary but not sufficient.While these risk factors are highly relevant, they do not, on their own,predict who will develop PML, since the vast majority of individualswith these risk factors will not develop the disorder. Other factorsneed to be considered and there is growing evidence for the role of hostgenetic factors in susceptibility to PML.

The ability to more accurately predict who is at risk of developing PMLwill be of enormous benefit in the context of drug treatment withcompounds that are highly effective in their disease context(natalizumab in MS, for example) but carry a risk of a devastatingdisorder. There is a need to develop a companion diagnostic testing, inorder to effectively exclude those that were at risk of PML, in theprocess reassuring those with negative tests about their dramaticallyreduced risk of developing PML.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.In the event of a conflict between a term herein and a term incorporatedby reference, the term herein controls.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the disclosure are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present disclosure will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the disclosure are utilized, andthe accompanying drawings.

FIG. 1 represents an example of a gene (PRKCB) impacted by germline andacquired CNVs.

FIG. 2 represents an example of genes (TNFRSF13C and CENPM) impacted byacquired CNVs.

FIG. 3 represents an example of a gene (PKHD1) impacted by germline andacquired CNVs.

FIG. 4 represents an example of a gene (BMPR2) impacted by a CNV(homozygous and heterozygous losses).

FIG. 5 represents an example of a gene (COMMD6) impacted by a CNV (e.g.,homozygous duplication).

FIG. 6 represents an example of genes (KCTD7, RABGEF1) directly andpotentially impacted by a CNV (e.g., homozygous duplication).

FIG. 7 represents an example of a gene (FPR2) impacted by a CNV (e.g.,homozygous duplication).

FIG. 8 represents an example of a gene (PIK3CD) impacted by a CNV (e.g.,homozygous loss).

FIG. 9 represents an example of a gene (CD180) potentially impacted byan intergenic CNV gain (e.g., homozygous duplication).

FIG. 10 represents an example of a gene (VDAC1) potentially impacted byan intergenic CNV (homozygous loss).

FIG. 11 represents an example of genes (EGR1 and ETF1) potentiallyimpacted by an intergenic CNV (homozygous loss).

FIG. 12 represents an example of a gene (ITSN2) potentially impacted byan intergenic CNV (homozygous loss).

FIG. 13 represents an example of known and/or predicted proteininteractions using the String database for 21 of 43 genes (non-redundantlist) reported in Table 7. The number of PML cases found to harborvariants impacting a given gene is indicated next to each gene.

FIG. 14 represents an example gene set analysis of protein-proteininteractions using the String database described herein. The input genelist was 74 genes (see Table 42) and the largest network from the Stringdatabase analysis output, a 24-gene network, is depicted. The genes arecolor-coded based on the GO pathway ID with the largest number of genes(26) that was in the top 5 GO results: GO:0006955, dark gray coloredgenes.

SUMMARY OF THE INVENTION

Provided herein is a method of treating a condition in a subject in needthereof, comprising: administering a therapeutically effective amount ofone or more immunosuppressive medications to the subject, wherein thesubject is identified as not having a high risk of developingprogressive multifocal leukoencephalopathy (PML) by a genetic test. Insome embodiments, the subject is identified as not having a risk ofdeveloping PML by a genetic test.

Provided herein is a method of treating a condition in a subject in needof immunosuppressive medication therapy, comprising: administering atherapeutically effective amount of one or more immunosuppressivemedications to the subject, wherein the subject has a decreased risk ofprogressive multifocal leukoencephalopathy (PML) due to an infection ofthe brain by John Cunningham virus (JCV), wherein the subject'sdecreased risk is due to the absence of one or more genetic variationsthat occur at a frequency of 100% or less in a population of humansubjects with PML. In some cases, the one or more genetic variationsoccur at a frequency of 100% or less, for example, 90% or less, 80% orless, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less,20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% orless, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9%or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% orless, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% orless, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less,0.002% or less, or 0.001% or less in a population of human subjects withPML. In some cases, the one or more genetic variations occur at afrequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5%to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%,or from 0.00001% to 0.001% in a population of human subjects with PML.

In some embodiments, the risk is due to the absence of one or moregenetic variations that occur at a frequency of 100% or less in apopulation of human subjects with PML and with an immune deficiency. Insome cases, the one or more genetic variations occur at a frequency of100% or less, for example, 90% or less, 80% or less, 70% or less, 60% orless, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less,9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less,3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% orless, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% orless, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02%or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% orless in a population of human subjects with PML and with an immunedeficiency. In some cases, the one or more genetic variations occur at afrequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5%to 10%, from 1% to 5%, from 0.5% to 10%, from 0.1% to 0.5%, from 0.05%to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to0.005%, or from 0.00001% to 0.001% in a population of human subjectswith PML and with an immune deficiency.

The immune deficiency can be X-linked agammaglobulinemia (XLA), commonvariable immunodeficiency (CVID), severe combined immunodeficiency(SCID), acquired immune deficiency syndrome (AIDS), cancers of theimmune system (e.g., leukemia), immune-complex diseases (e.g., viralhepatitis), or multiple myeloma.

In some embodiments, the subject's decreased risk is due to the absenceof one or more genetic variations that occur at a frequency of 100% orless in a population of human subjects with PML and without an immunedeficiency. In some cases, the one or more genetic variations occur at afrequency of 100% or less, for example, 90% or less, 80% or less, 70% orless, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less,10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less,4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% orless, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% orless, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% orless, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or0.001% or less in a population of human subjects with PML and without animmune deficiency. In some cases, the one or more genetic variationsoccur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%,from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from0.001% to 0.005%, or from 0.00001% to 0.001% in a population of humansubjects with PML and without an immune deficiency.

Provided herein is a method of treating a condition in a subject in needof immunosuppressive medication therapy, comprising: administering atherapeutically effective amount of one or more immunosuppressivemedications to the subject, wherein the subject has a decreased risk ofprogressive multifocal leukoencephalopathy (PML) due to an infection ofthe brain by John Cunningham virus (JCV), and wherein the subject'sdecreased risk is due to the absence of one or more genetic variationsthat occur at a frequency of 100% or less in a population of humansubjects without PML. In some cases, the one or more genetic variationsoccur at a frequency of 100% or less, for example, 90% or less, 80% orless, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less,20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% orless, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9%or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% orless, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% orless, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less,0.002% or less, or 0.001% or less in a population of human subjectswithout PML. In some cases, the one or more genetic variations occur ata frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05%to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to0.005%, or from 0.00001% to 0.001% in a population of human subjectswithout PML.

In some embodiments, the risk is due to the absence of one or moregenetic variations that occur at a frequency of 100% or less in apopulation of human subjects without PML and with an immune deficiency.In some cases, the one or more genetic variations occur at a frequencyof 100% or less, for example, 90% or less, 80% or less, 70% or less, 60%or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% orless, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% orless, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less,0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less,0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less,0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001%or less in a population of human subjects without PML and with an immunedeficiency. In some cases, the one or more genetic variations occur at afrequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5%to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%,or from 0.00001% to 0.001% in a population of human subjects without PMLand with an immune deficiency.

In some embodiments, the risk is due to the absence of one or moregenetic variations that occur at a frequency of 100% or less in apopulation of human subjects without PML and without an immunedeficiency. In some cases, the one or more genetic variations occur at afrequency of 100% or less, for example, 90% or less, 80% or less, 70% orless, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less,10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less,4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% orless, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% orless, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% orless, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or0.001% or less in a population of human subjects without PML and withoutan immune deficiency. In some cases, the one or more genetic variationsoccur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%,from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from0.001% to 0.005%, or from 0.00001% to 0.001% in a population of humansubjects without PML and without an immune deficiency.

Provided herein is a method of treating a condition in a subject in needof immunosuppressive medication therapy, comprising: administering atherapeutically effective amount of one or more immunosuppressivemedications to the subject, wherein the subject has a decreased risk ofprogressive multifocal leukoencephalopathy (PML) due to an infection ofthe brain by John Cunningham virus (JCV), and wherein the risk is due tothe absence of one or more genetic variations that occur at a frequencyof 100% or less in a population of human subjects with an immunedeficiency. In some cases, the one or more genetic variations occur at afrequency of 100% or less, for example, 90% or less, 80% or less, 70% orless, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less,10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less,4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% orless, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% orless, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% orless, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or0.001% or less in a population of human subjects with an immunedeficiency. In some cases, the one or more genetic variations occur at afrequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5%to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%,or from 0.00001% to 0.001% in a population of human subjects with animmune deficiency.

In some embodiments, the risk is due to the absence of one or moregenetic variations that occur at a frequency of 100% or less in apopulation of human subjects with an immune deficiency and with PML. Insome embodiments, the risk is due to the absence of one or more geneticvariations that occur at a frequency of 100% or less in a population ofhuman subjects with an immune deficiency and without PML.

Provided herein is a method of treating a condition in a subject in needof immunosuppressive medication therapy, comprising: administering atherapeutically effective amount of one or more immunosuppressivemedications to the subject, wherein the subject has a decreased risk ofprogressive multifocal leukoencephalopathy (PML) due to an infection ofthe brain by John Cunningham virus (JCV), and wherein the subject'sdecreased risk is due to the absence of one or more genetic variationsthat occur at a frequency of 100% or less in a population of humansubjects without an immune deficiency. In some cases, the one or moregenetic variations occur at a frequency of 100% or less, for example,90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% orless, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7%or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1%or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% orless, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% orless, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005%or less, 0.002% or less, or 0.001% or less in a population of humansubjects without an immune deficiency. In some cases, the one or moregenetic variations occur at a frequency of from 60% to 100%, from 30% to60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%,from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005%to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in apopulation of human subjects without an immune deficiency.

In some embodiments, the risk is due to the absence of one or moregenetic variations that occur at a frequency of 100% or less in apopulation of human subjects without an immune deficiency and with PML.In some embodiments, the risk is due to the absence of one or moregenetic variations that occur at a frequency of 100% or less in apopulation of human subjects without an immune deficiency and withoutPML.

Provided herein is a method of treating a condition in a subject in needof immunosuppressive medication therapy, comprising: administering atherapeutically effective amount of one or more immunosuppressivemedications to the subject, wherein the subject has a decreased risk ofprogressive multifocal leukoencephalopathy (PML) due to an infection ofthe brain by John Cunningham virus (JCV), wherein the subject'sdecreased risk is due to the absence of one or more genetic variationsin the subject, wherein the one or more genetic variations have an oddsratio (OR) of 1.1 or more, and wherein the OR is:[D_(D)/D_(N)]/[N_(D)/N_(N)], wherein: D_(D) is the number of subjects ina diseased cohort of subjects with the one or more genetic variations;D_(N) the number of subjects in the diseased cohort without the one ormore genetic variations; N_(D) is the number of subjects in anon-diseased cohort of subjects with the one or more genetic variations;and N_(N) is the number of subjects in the non-diseased cohort withoutthe one or more genetic variations. In some embodiments, the subject'sdecreased risk is due to the absence of one or more genetic variationsthat has an odds ratio (OR) of at least 1.1, for example, at least 1.2,at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, atleast 1.8, at least 1.9, at least 2, at least 3, at least 4, at least 5,at least 6, at least 7, at least 8, at least 9, at least 10, at least15, at least 20, at least 25, at least 30, at least 35, at least 40, atleast 45, at least 50, at least 60, at least 70, at least 80, at least90, at least 100, at least 150, at least 200, at least 250, at least300, at least 350, at least 400, at least 450, at least 500, at least600, at least 700, at least 800, at least 900, at least 1000, at least1100, at least 1200, at least 1300, at least 1400, or at least 1500. Inanother embodiment, the subject's decreased risk is due to the absenceof one or more genetic variations that has an OR of infinite whereinN_(D) is 0 (the one or more genetic variations are not found in thenon-diseased cohort). In another embodiment, ND can be set to 1 whencalculating OR if the one or more genetic variations are not found inthe non-diseased cohort. In some embodiments, the one or moreimmunosuppressive medications comprise natalizumab.

In some embodiments, the cohort comprises at least 100 human subjects.In some embodiments, the at least 100 human subjects comprises at least10 human subjects with PML, at least 10 human subjects with an immunedeficiency, at least 10 human subjects without an immune deficiency, atleast 10 human subjects without PML, or any combination thereof. In someembodiments, the diseased cohort comprises at least 10, 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 human subjectswith PML, with an immune deficiency, or both. In some embodiments, thenon-diseased cohort comprises at least 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 human subjects withoutPML, without an immune deficiency, or both. In some embodiments, thehuman subjects in the cohort are the same ethnicity (e.g., Africanancestry, European ancestry). In some embodiments, the human subjects inthe cohort are different ethnicities. In some embodiments, the humansubjects in the cohort are the same gender. In some embodiments, thehuman subjects in the cohort are different genders. In some embodiments,the diseased cohort of subjects, the non-diseased cohort of subjects, orboth cohorts of subjects are ethnically matched. In some embodiments,the diseased cohort of subjects, the non-diseased cohort of subjects, orboth cohorts of subjects are not ethnically matched.

Provided herein is a method of treating a condition in a subject in needof immunosuppressive medication therapy, comprising: administering atherapeutically effective amount of one or more immunosuppressivemedications to a subject with a condition, wherein the subject has adecreased risk of progressive multifocal leukoencephalopathy (PML) dueto an infection of the brain by John Cunningham virus (JCV), wherein thesubject's decreased risk is due to the presence of genetic sequencesthat do not comprise any of 2 or more genetic variations in a panelcomprising the 2 or more genetic variations.

In some embodiments, the 2 or more genetic variations comprise at least3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50,75, 100 genetic variations. In some embodiments, the genetic sequencesare wild-type genetic sequences. In some embodiments, the geneticsequences are wild-type genetic sequences comprising one or more silentmutations. In some embodiments, the one or more silent mutationscomprise a mutation in a non-coding region. In some embodiments, the oneor more silent mutations comprise a mutation in an exon that does notresult in a change to the amino acid sequence of a protein (synonymoussubstitution).

In some embodiments, the condition is a cancer, an organ transplant, oran autoimmune disease.

In some embodiments, the condition is an autoimmune disease.

In some embodiments, the autoimmune disease is selected from the groupconsisting of Addison disease, Anti-NMDA receptor encephalitis,antisynthetase syndrome, Aplastic anemia, autoimmune anemias, Autoimmunehemolytic anemia, Autoimmune pancreatitis, Behcet's Disease, bullousskin disorders, Celiac disease-sprue (gluten-sensitive enteropathy),chronic fatigue syndrome, Chronic inflammatory demyelinatingpolyneuropathy, chronic lymphocytic leukemia, Crohn's disease,Dermatomyositis, Devic's disease, Erythroblastopenia, Evans syndrome,Focal segmental glomerulosclerosis, Granulomatosis with polyangiitis,Graves disease, Graves' ophthalmopathy, Guillain-Barre syndrome,Hashimoto thyroiditis, idiopathic thrombocytopenic purpura (ITP), IgAnephropathy, IgA-mediated autoimmune diseases, IgG4-related disease,Inflammatory bowel disease, Juvenile idiopathic arthritis, Multiplesclerosis, Myasthenia gravis, myeloma, non-Hodgkin's lymphoma,Opsoclonus myoclonus syndrome (OMS), Pemphigoid, Pemphigus, pemphigusvulgaris, Pernicious anemia, polymyositis, Psoriasis, pure red cellaplasia, Reactive arthritis, Rheumatoid arthritis, Sarcoidosis,scleroderma, Sjögren syndrome, Systemic lupus erythematosus,Thrombocytopenic purpura, Thrombotic thrombocytopenic purpura, Type Idiabetes, Ulcerative colitis, Vasculitis (e.g., vasculitis associatedwith anti-neutrophil cytoplasmic antibody), Vitiligo, and combinationsthereof.

In some embodiments, the autoimmune disease is multiple sclerosis orCrohn's disease. In some embodiments, the autoimmune disease is multiplesclerosis. In some embodiments, the multiple sclerosis is a relapsingform of multiple sclerosis. In some embodiments, the multiple sclerosisis relapsing-remitting multiple sclerosis (RRMS). In some embodiments,the multiple sclerosis is primary progressive multiple sclerosis (PPMS).In some embodiments, the multiple sclerosis is secondary progressivemultiple sclerosis (SPMS).

In some embodiments, the one or more immunosuppressive medicationscomprise a glucocorticoid, cytostatic, antibody, drug acting onimmunophilins, interferon, opioid, TNF binding protein, mycophenolate,small biological agent, small molecule, organic compound, or anycombination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic(AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4,anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent,anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb,anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctionalfusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 andanti-LAG3 mAb, CDId ligand, CD40 agonist, Complement C5a inhibitor,CSFIR inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor,FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factorreceptor-related gene [GITR] agonist, glutaminase inhibitor, Humanmonoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptortyrosine kinase inhibitor, neutrophil elastase inhibitor, NotchInhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L,ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator,Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combinationthereof.

In some embodiments, the one or more immunosuppressive medicationscomprise abatacept (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab,adrenocorticotropic hormone, agatolimod sodium, AJM300, aldesleukin,alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride,alvocidib, ambrisentan (e.g. LETAIRIS), aminocamptothecin, amiselimod,anakinra, andecaliximab, andrographolides (a botanical medicinal herbalso known as IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib,asparaginase, atacicept, atezolizumab, avelumab, azacitidine,azathioprine, bafetinib, baminercept, baricitinib, basiliximab,becatecarin, begelomab, belatacept, belimumab, bemeentinib,bendamustine, bendamustine (e.g. bendamustine hydrochloride), betalutinwith lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab,binimetinib, bleomycin, blinatumomab, BNZ-1, bortezomib (e.g. VELCADE),brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan,canakinumab, capecitabine, carboplatin, carfilzomib, carmustine,cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab(e.g. certolizumab pegol), cetuximab, chidamide, chlorambucil, CHS-131,cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab,clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine,cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine (e.g.AMPYRA), daprolizumab pegol, daratumumab, dasatinib, defactinib,defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate,dinaciclib, diroximel fumarate (e.g. VUMERITY), doxorubicin, doxorubicin(e.g. doxorubicin hydrochloride), durvalumab, duvelisib, duvortuxizumab,eculizumab (e.g. SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (aneuropeptide combination of metenkefalin and tridecactide), elezanumab,elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g. FUZEON),entinostat, entospletinib, enzastaurin, epacadostat, epirubicin,epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab,everolimus, evobrutinib, filgotinib, fingolimod (e.g. fingolimodhydrochloride), firategrast, fludarabine, fluorouracil, fontolizumab,forodesine hydrochloride, fostamatinib, galunisertib, ganetespib,ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib,glassia, glatiramer acetate, glembatumumab vedotin, glesatinib,golimumab (e.g. SIMPONI), guadecitabine, hydrocortisone,hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan,ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide,iguratimod, imatinib, imexon, IMU-838, infliximab, inotuzumabozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b,interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib,itacitinib, ixazomib, lapatinib, laquinimod, laromustine,ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole (e.g.FEMARA), levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib,lumiliximab, maraviroc (e.g. SELZENTRY), masitinib, mavrilimumab,melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone,milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab,mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox,muromonab-CD3, mycophenolate mofetil (e.g. mycophenolate mofetilhydrochloride), mycophenolic acid, namilumab, natalizumab, navitoclax,neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclaxmesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab,olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab,oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib,palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim (e.g.NEULASTA), peginterferon beta-1a, pegsunercept (peg stnf-ri),pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine,pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex,pixantrone, pleneva, plovamer acetate, polatuzumab vedotin,pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide,R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant il-12,relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir (e.g.NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246, sarilumab,secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod(e.g. MAYZENT), sirolimus (rapamycin), sirukumab, sitravatinib,sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenonepigallocatechin-gallate, tabalumab, tacrolimus (e.g. tacrolimusanhydrous), talabostat mesylate, talacotuzumab, tanespimycin,tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib,terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa,tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab,tofacitinib, TR-14035, tregalizumab, tremelimumab, treosulfan,ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab,varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax,vinblastine, vincristine, vinorelbine ditartrate, visilizumab,vismodegib, vistusertib, voriconazole (e.g. VFEND), vorinostat,vosaroxin, ziv-aflibercept, or any combination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise 2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoicacid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501,ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555,ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452,Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884,AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803,ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APLA12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797,ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASN002, ASP015K,ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188,ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991,AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312,BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100,BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492,BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, BIBR 796BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564,BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205,BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061,BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088,CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323,CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116,CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131,CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102,CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP,DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555,DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIA11, EOC202,ETBX-011, F8IL10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327,FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853,GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L,GS-1011, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249,GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781,GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769,GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286,HL2351, HL237, hLL1-DOX (IMMU-115), HLXO1, HM71224, HMPL-523, HSC835,HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125,INCAGNO2385, INCB018424, INCB028050, INCB039110, INCB047986,rNCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056,ISF35, ISIS 104838, ITF2357, JCARH125, JHLI 101, JNJ 38518168,JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011,KB003, KD025, KPT-330, KW-2449, KW-247&, KX2-391, L-778123, LAG525,LAM-002A, LBECO101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399,LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367,LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013,MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538,MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280,MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812,MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibodyM-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022,MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303,MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071,NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012,NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNC0215-0384,NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON01910 Na,ONO-2506PO, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05,PBF-509, PBR06, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001,PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586,PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600,PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326,PRO131921, PR0283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001,RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077,RGB-03, RGI-2001, RHB-104, RNS60, R05045337, R07123520, Rob 803,RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323,SB683699, SBI-087, SC12267 (4SC-101), SCH 727965, SCIO-469, SD-101,SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136,SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996,SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023,SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901,TGR-1202, TH-302, TLO11, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015,TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R,VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844,XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365, or anycombination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab, diroximel fumarate, siponimod or any combination thereof.

In some embodiments, the subject has not taken the one or moreimmunosuppressive medications. In some embodiments, the subject hastaken the one or more immunosuppressive medications. In someembodiments, the subject is taking the one or more immunosuppressivemedications.

In some embodiments, the one or more immunosuppressive medicationscomprise natalizumab (e.g., TYSABRI). In some embodiments, at leastabout 10 mg of the natalizumab is administered, for example, at leastabout 10 mg, at least about 15 mg, at least about 20 mg, at least about30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg,at least about 70 mg, at least about 80 mg, at least about 90 mg, atleast about 100 mg, at least about 150 mg, at least about 200 mg, atleast about 250 mg, or at least about 300 mg of the natalizumab isadministered. In some embodiments, at least about 10 mg of thenatalizumab is administered via intravenous infusion. In someembodiments, at least about 10 mg of the natalizumab is administered viaintravenous infusion in four weeks. In some embodiments, about 100 mg toabout 500 mg of the natalizumab is administered, for example, about 100mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg,about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mgto about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about500 mg of the natalizumab is administered. In some embodiments, about100 mg to about 500 mg of the natalizumab is administered viaintravenous infusion. In some embodiments, about 100 mg to about 500 mgof the natalizumab is administered via intravenous infusion in fourweeks. In some embodiments, about 300 mg of the natalizumab isadministered. In some embodiments, about 300 mg of the natalizumab isadministered via intravenous infusion. In some embodiments, about 300 mgof the natalizumab is administered via intravenous infusion in fourweeks. In some embodiments, at least about 10 mg of the natalizumab isadministered via intravenous infusion in six weeks. In some embodiments,at least about 10 mg of the natalizumab is administered via intravenousinfusion in eight weeks. In some embodiments, about 100 mg to about 500mg of the natalizumab is administered via intravenous infusion in sixweeks. In some embodiments, about 100 mg to about 500 mg of thenatalizumab is administered via intravenous infusion in eight weeks. Insome embodiments, about 300 mg of the natalizumab is administered viaintravenous infusion in six weeks. In some embodiments, about 300 mg ofthe natalizumab is administered via intravenous infusion in eight weeks.

In some embodiments, the one or more immunosuppressive medicationscomprise dimethyl fumarate. In some embodiments, about 100 mg to about500 mg of the dimethyl fumarate is administered, for example, about 100mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg,about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mgto about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about500 mg of the dimethyl fumarate is administered. In some embodiments,about 120 mg of the dimethyl fumarate is administered. In someembodiments, about 240 mg of the dimethyl fumarate is administered.

In some embodiments, the one or more immunosuppressive medicationscomprise diroximel fumarate. In some embodiments, the one or moreimmunosuppressive medications comprise diroximel fumarate. In someembodiments, about 100 mg to about 500 mg of the diroximel fumarate isadministered, for example, about 100 mg to about 200 mg, about 100 mg toabout 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500mg, about 200 mg to about 300 mg, about 200 mg to about 400 mg, about200 mg to about 500 mg, about 300 mg to about 400 mg, about 300 mg toabout 500 mg, or about 400 mg to about 500 mg of the diroximel fumarateis administered. In some embodiments, about 400, 410, 420, 430, 440,450, 460, 462, 470, 480, 490 or 500 mg of the diroximel fumarate isadministered.

In some embodiments, the one or more immunosuppressive medicationscomprise fingolimod. In some embodiments, about 0.01 mg to about 5 mg ofthe fingolimod is administered, for example, about 0.01 mg to about 2mg, about 0.01 mg to about 3 mg, about 0.01 mg to about 4 mg, about 0.01mg to about 5 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 3mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 5 mg, about 0.2 mgto about 3 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 5 mg,about 0.3 mg to about 4 mg, about 0.3 mg to about 5 mg, about 0.4 mg toabout 5 mg, about 0.1 mg to about 0.2 mg, about 0.1 mg to about 0.3 mg,about 0.1 mg to about 0.4 mg, about 0.1 mg to about 0.5 mg, about 0.2 mgto about 0.3 mg, about 0.2 mg to about 0.4 mg, about 0.2 mg to about 0.5mg, about 0.3 mg to about 0.4 mg, about 0.3 mg to about 0.5 mg, about0.4 mg to about 0.5 mg, or about 0.4 mg to about 0.6 mg of thefingolimod is administered. In some embodiments, about 0.25 mg or 0.5 mgof the fingolimod is administered.

In some embodiments, the one or more immunosuppressive medicationscomprise rituximab. In some embodiments, about 100 mg to about 1000 mgof the rituximab is administered, for example, about 100 mg to about 200mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about100 mg to about 500 mg, about 100 mg to about 600 mg, about 100 mg toabout 700 mg, about 100 mg to about 800 mg, about 100 mg to about 900 mgof the rituximab is administered. The dose may be by weight or a fixeddose. In some embodiments, about 250 mg/m², 375 mg/m², 500 mg/m², 500mg, or 1000 mg of the rituximab is administered. In some embodiments,about 250 mg/m², 375 mg/m², 500 mg/m², 500 mg, or 1000 mg of therituximab is administered every week, every 2 weeks, every 4 weeks,every 8 weeks, or every 6 months. In some embodiments, about 250 mg/m²,375 mg/m², 500 mg/m², 500 mg, or 1000 mg of the rituximab isadministered every 8 weeks or every 6 months for treating MS. The totaldose can be from about 50 and 4000 mg, for example, from about 75 and3000 mg, from about 100 and 2000 mg, from about 100 and 1000 mg, fromabout 150 and 1000 mg, or from about 200 and 1000 mg, including doses ofabout 200, 300, 400, 500, 600, 700, 800, 900, 1000 mg, and 2000 mg.These doses may be given as a single dose or as multiple doses, forexample, two to four doses. Such doses may be done by infusions, forexample.

In some embodiments, the one or more immunosuppressive medicationscomprise siponimod. In some embodiments, about 0.1 mg to about 5 mg ofthe siponimod is administered. In some embodiments, about 1 mg or about2 mg of the siponimod is administered. In some embodiments, about 1 mgor about 2 mg of the siponimod is administered to a subject with aCYP2C9*1/*3 or CYP2C9*2/*3 genotype.

In some embodiments, the subject does not have one or more geneticvariations associated with a risk of developing PML. In someembodiments, the subject does not have one or more genetic variationsassociated with a high risk of developing PML.

In some embodiments, the genetic test comprises detecting one or moregenetic variations associated with a risk of developing PML in apolynucleic acid sample from the subject. In some embodiments, thegenetic test comprises detecting one or more genetic variationsassociated with a high risk of developing PML in a polynucleic acidsample from the subject.

In some embodiments, the one or more genetic variations comprise a pointmutation, polymorphism, single nucleotide polymorphism (SNP), singlenucleotide variation (SNV), translocation, insertion, deletion,amplification, inversion, interstitial deletion, copy number variation(CNV), structural variation (SV), loss of heterozygosity, or anycombination thereof.

In some embodiments, the one or more genetic variations disrupt ormodulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26,29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of treating a condition in a subject in needof natalizumab, interferon beta-1a, interferon beta-1b, glatirameracetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethylfumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab,diroximel fumarate or siponimod therapy, comprising: administering atherapeutically effective amount of natalizumab, interferon beta-1a,interferon beta-1b, glatiramer acetate, peginterferon beta-1a,teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone,rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod tothe subject, wherein the subject is identified as not having one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48.

Provided herein is a method of reducing a risk of a subject developingprogressive multifocal leukoencephalopathy (PML) comprisingadministering a therapeutically effective amount of natalizumab to thesubject, wherein the subject is identified as not having one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48.

In some embodiments, the condition is multiple sclerosis.

In some embodiments, the condition is Crohn's disease.

Provided herein is a method of treating multiple sclerosis comprisingadministering natalizumab, interferon beta-1a, interferon beta-1b,glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod,dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab,ocrelizumab, diroximel fumarate or siponimod to a subject with multiplesclerosis, wherein the subject is identified as not having one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48.

Provided herein is a method of treating Crohn's disease comprisingadministering natalizumab, interferon beta-1a, interferon beta-1b,glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod,dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab,ocrelizumab, diroximel fumarate or siponimod to a subject with Crohn'sdisease, wherein the subject is identified as not having one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48.

Provided herein is a method of treating multiple sclerosis comprisingtesting a subject with multiple sclerosis for the presence of one ormore genetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48, determining that the subject does not have the one ormore genetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48, and administering natalizumab to the subject that wasdetermined not to have the one or more genetic variations that disruptor modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26,29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of treating Crohn's disease comprisingtesting a subject with Crohn's disease for the presence of one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48, determining that the subject does not have the one ormore genetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48, and administering natalizumab to the subject that wasdetermined not to have the one or more genetic variations that disruptor modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26,29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of reducing a risk of a subject developingprogressive multifocal leukoencephalopathy (PML) comprising testing asubject for the presence of one or more genetic variations that disruptor modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26,29, 31 and 48; or Tables 3, 6, 29, 31 and 48, determining that thesubject has at least one of the one or more genetic variations thatdisrupt or modulate a corresponding gene according to Tables 3, 6, 25A,25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, and advisingagainst administering natalizumab, interferon beta-1a, interferonbeta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide,fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab,daclizumab, ocrelizumab, diroximel fumarate or siponimod to the subjectthat was determined to have at least one of the one or more geneticvariations that disrupt or modulate a corresponding gene according toTables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

In some embodiments, the subject has multiple sclerosis.

In some embodiments, the subject has Crohn's disease.

Provided herein is a method of treating multiple sclerosis comprisingtesting a subject with multiple sclerosis for the presence of one ormore genetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48, determining that the subject has at least one of the oneor more genetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48, and advising against administering natalizumab to thesubject that was determined to have at least one of the one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48.

Provided herein is a method of treating Crohn's disease comprisingtesting a subject with Crohn's disease for the presence of one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48, determining that the subject has at least one of the oneor more genetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48, and advising against administering natalizumab to thesubject that was determined to have at least one of the one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48.

In some embodiments, the advising comprises advising that administeringnatalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximelfumarate or siponimod is contraindicated.

In some embodiments, the advising comprises advising that administeringnatalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximelfumarate or siponimod increases the risk of the subject developingprogressive multifocal leukoencephalopathy (PML)

In some embodiments, the advising comprises advising that administeringnatalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximelfumarate or siponimod is a factor that increases the risk of the subjectdeveloping progressive multifocal leukoencephalopathy (PML).

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene according to Table 13.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene according to Table 14.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene according to Table 15.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene according to Table 16.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene according to Table 17.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene according to Table 18.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of ALG12, AP3B1,ASHIL, ATL2, ATM, ATR, BACH1, BLM, CHD7, CLCN7, CR2, CX3CR1, DOCK2,DOCK8, EHF, EPG5, FAS, FUK, GFI1, GOLGB1, GTPBP4, HIVEP1, HIVEP2,HIVEP3, IFIH1, IGLL1, IL10, IL12B, IL17F, ITK, ITSN2, JAGN1, KITLG,LRBA, LYST, MALT1, MAVS, MCEE, NHEJ1, NOD2, NRIP1, ORAI1, PGM3, PIK3CD,PLCG2, PNP, POLE, PRF1, RBCK1, RBFOX1, RNASEL, RTEL1, SALL2, SHARPIN,SNAP29, STIM2, STXBP2, TAP1, TBCID16, TCIRG1, TICAM1, TMEM173,TNFRSF10A, TTC7A, VPS13B, and combinations thereof.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of ACD, ADGRL2,AIRE, ATG5, ATG7, BLK, BRD4, C3, C7, C8A, C8B, C9, CAMLG, CCBE1, CCZ1,CD22, CD36, CD37, CD5, CD72, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5,CFTR, CHD2, CLEC16A, CLPB, COPA, CTC1, DNAJC21, EGF, ERCC6L2, FAT4,FCER2, HERC5, HERC6, ICAM1, IFI35, IFIT1, IFIT3, IL4, ITSN1, KMT2D,KRAS, LRRK2, MASP2, MBL2, MCM5, MDC1, MFN2, MLH1, MMP9, MOGS, MONIA,MON1B, MSH2, MSH5, MX1, MX2, MYSM1, NBAS, NCF1, NCF2, NCF4, NFAT5,NLRP2, NLRX1, NOD1, OAS1, OAS2, OAS3, ORC4, PARN, PEPD, PINK1, PLAU,PLAUR, PLCG1, PLD1, PLEKHM1, PLK1, PLXNB1, PRRC2A, RAB5A, RAB5B, RAD50,RANBP2, RELA, RLTPR, RNF125, RPSA, RSAD2, SAMD9, SAMD9L, SERPINA1,SERPINB2, SMARCAL1, SMURF2, SRP54, TBC1D17, TCN2, TEK, TFPI, TMC8,TP53AIP1, TRAF3IP2, USB1, USP3, VEGFA, WASHC5, WRAP53, and XAF1.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PLCG2, RBCK1,EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2,NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2, ALG12,and combinations thereof.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PLCG2, IFIH1,TCIRG1, IGLL1, MAVS, SHARPIN, CHD7, CX3CR1, LRBA, HIVEP3, RNASEL, andcombinations thereof.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of SHARPIN, RTEL1,PGM3, TMEM173, CLCN7, MAVS, ORAI1, RBFOX1, MALT1, GFI1, DOCK2, ATM,SNAP29, TICAM1, GTPBP4, BACH1, STXBP2, FAS, GOLGB1, FUK, IL10, ITK,STIM2, ASHIL, TBCID16, LYST, SALL2, CHD7, BLM, NOD2, IGLL1, TTC7A,KITLG, ATR, ATM, CR2, HIVEP2, ITSN2, DOCK8, VPS13B, NRIP1, andcombinations thereof.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of SHARPIN, IFIH1,PLCG2, CHD7, and combinations thereof.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PLCG2, POLE,LRBA, EPG5, SHARPIN, and combinations thereof.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PLCG2, RBCK1,EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2,NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2, ALG12,FCN2, LY9 and PRAM1.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of FCN2, LY9 andPRAM1

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of AIRE, ATM, C8B,CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IFIH1, IGLL1, LIG1,LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PLCG2, PRAM1, SERPINA1, STXBP2, TAP1and TCIRG1.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of AIRE, ATM, C8B,CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IGLL1, LIG1, LRBA, LY9,MCM5, MDC1, NQO2, PKHD1, PRAM1, SERPINA1, and TAP1.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of IGLL1, MDC1,STXBP2, FCN2, IGLL1, MCM5 and IFIH1.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PRAM1, ATM,TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of IGLL1, MDC1,STXBP2, PRAM1, ATM, FCN2, IGLL1, MCM5, IFIH1, TAP1, PLCG2, FCN3, DNER,SERPINA1 and LRBA.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PRAM1, HIVEP3and TCIRG1.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of LY9, LIG1,PKHD1, AIRE, GFI1, CFHR2, NQO2, PRAM1, C8B, DNASE1L3, PLCG2, HIVEP3 andTCIRG1.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PKHD1, LY9,CFHR2, NQO2, AIRE, IGLL1, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2 andPLCG2.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of TAP1, GFI1,IGLL1, MCM5, IFIH1, FCN3, SERPINA1

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PLCG2, CHD7,IFIH1, AP3B1, EPG5, PIK3CD, LRBA, SHARPIN, and combinations thereof.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of PKHD1, LY9,CFHR2, NQO2, AIRE, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2, PLCG2, TAP1,GFI1, IGLL1, MCM5, IFIH1, FCN3 and SERPINA1.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of LY9, PKHD1,AIRE, CFHR2, NQO2, IGLL1, PRAM1, MDC1, FCN2, STXBP2, TCIRG1 and PLCG2.

In some embodiments, the testing comprises testing the subject for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene selected from the group consisting of LIG1, MCM5,GFI1, IFIH1, IGLL1, ATM, TAP1, FCN3, LRBA and SERPINA1.

In some embodiments, the subject is identified as not having a risk ofdeveloping progressive multifocal leukoencephalopathy (PML) by a genetictest. In some embodiments, the subject is identified as not having ahigh risk of developing progressive multifocal leukoencephalopathy (PML)by a genetic test.

In some embodiments, the testing comprises assaying a polynucleic acidsample from the subject for the one or more genetic variations.

In some embodiments, the one or more genetic variations result in a lossof function of the corresponding gene.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN1-GN765.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) 1-156 (in Table 3).

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) in Table 6.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN491-GN492 in Table 29.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN493-GN762 in Table 31.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN763-GN765 in Table 48.

In some embodiments, the corresponding gene comprises a gene selectedfrom Tables 34-40, 42, 45A, 45B, 45C, 48, 50A, 50B and 51-62.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1,JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1,TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2 and ALG12 (see Table 13).

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1,JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1,TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2, ALG12, FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER,FCN2, FCN3, GFI1, HIVEP3, IFIH1, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1,NQO2, PKHD1, PLCG2, PRAM1, SERPINA1, STXBP2, TAP1 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting ofAIRE, ATM, C8B, CFHR2, DNASE1L3, DNER, FCN2,FCN3, GFI1, HIVEP3, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1, NQO2, PKHD1,PRAM1, SERPINA1, and TAP1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of IGLL1, MDC1, STXBP2, FCN2, IGLL1, MCM5 andIFIH1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PRAM1, ATM, TAP1, PLCG2, FCN3, DNER,SERPINA1 and LRBA.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of IGLL1, MDC1, STXBP2, PRAM1, ATM, FCN2,IGLL1, MCM5, IFIH1, TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LY9, LIG1, PKHD1, AIRE, GFI1, CFHR2, NQO2,C8B, DNASE1L3 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PRAM1, HIVEP3 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LY9, LIG1, PKHD1, AIRE, GFI1, CFHR2, NQO2,PRAM1, C8B, DNASE1L3, PLCG2, HIVEP3 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, IGLL1,TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3,SERPINA1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, TCIRG1, ATM,MDC1, PRAM1, FCN2, STXBP2, PLCG2, TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3and SERPINA1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LY9, PKHD1, AIRE, CFHR2, NQO2, IGLL1,PRAM1, MDC1, FCN2, STXBP2, TCIRG1 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LIG1, MCM5, GFI1, IFIH1, IGLL1, ATM, TAP1,FCN3, LRBA and SERPINA1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LY9, PKHD1, AIRE, CFHR2, NQO2, IGLL1,PRAM1, MDC1, FCN2, STXBP2, TCIRG1, PLCG2, LIG1, MCM5, GFI1, IFIH1,IGLL1, ATM, TAP1, FCN3, LRBA and SERPINA1.

In some embodiments, the one or more genetic variations are encoded by asequence with at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, or at least 99% sequence identity to SEQ ID NOs 1-172 orSRN1-SRN363, with 100% sequence identity to SEQ ID NOs 1000-1329, orwith at least 80% and less than 100% sequence identity to GN1-GN490, orcomplements thereof.

In some embodiments, the one or more genetic variations are encoded by asequence with at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, or at least 99% sequence identity to SEQ ID NOs 1-172,2200-2203 or SRN1-SRN366, with 100% sequence identity to SEQ ID NOs1000-1329, 3000-3274, or with at least 80% and less than 100% sequenceidentity to GN1-GN765, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by asequence with at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203 orSRN364-SRN366, with 100% sequence identity to SEQ ID NOs 3000-3274, orwith at least 80% and less than 100% sequence identity to GN491-GN765,or complements thereof.

In some embodiments, the one or more genetic variations are encoded by asequence with at 100% sequence identity to SEQ ID NOs 3300-3351,3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NOs 1-172, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NOs 2200-2203, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV sub-region (SRN) with at least 60%,at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%sequence identity to SRN1-SRN363, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV sub-region (SRN) with at least 60%,at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%sequence identity to SRN364-SRN366, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NOs: 1000-1329, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NOs: 3000-3274, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NOs: 3300-3351, 3400-3467, 3500-3526, orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a sequence with at least 80% and less than100% sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a sequence with at least 80% and less than100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1011,1012, 1014, 1016, 1017, 1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036,1037, 1040, 1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062,1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076, 1077, 1078,1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1101, 1104, 1107, 1114,1116, 1118, 1121, 1122, 1123, 1125, 1126, 1127, 1128, 1129, 1130, 1131,1133, 1135, 1136, 1137, 1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154,1157, 1160, 1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176,1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200, 1201,1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226, 1227, 1228, 1229,1230, 1231, 1232, 1235, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254,1255, 1256, 1259, 1260, 1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279,1283, 1284, 1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311,1327 or 1328 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 3000-3274, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035,1036, 1040, 1056, 1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127,1135, 1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184, 1193,1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255, 1256, 1259, 1260,1261, 1263, 1273, 1278, 1279, 1284, 1287, 1289, 1299 or 1311 (see Table7), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012,1014, 1016, 1017, 1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058,1059, 1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076, 1078,1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104, 1107, 1116, 1118,1121, 1122, 1128, 1129, 1130, 1131, 1133, 1136, 1137, 1138, 1146, 1147,1150, 1152, 1160, 1161, 1165, 1166, 1168, 1169, 1171, 1175, 1176, 1177,1178, 1179, 1180, 1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220,1226, 1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250, 1251,1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286, 1290, 1291, 1300,1301, 1304, 1327 or 1328 (see Table 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr16:81942175A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T,chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,chr1:182554557 C>T, chr8:145154824 A>C, chr20:62305450 C>T,chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A,chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T,chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T,chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A,chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T,chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A,chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T,chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof(see Tables 14 and 15).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr16:81942175A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T,chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,chr1:182554557 C>T, and any combination thereof (see Table 14).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr8:145154824A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G,chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T,chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T,chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C,chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T,chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and anycombination thereof (see Table 15).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:196759282,C>T, chr4:126412634, C>G, chr10:75673748, A>C, chr6:30675830, T>A,chr6:30680721, G>A, chr12:56385915, GGGA>G, chr18:57103126, G>A,chr3:171321023, C>T, chr1:59131311, G>T, chr22:31008867, T>C,chr2:74690378, C>T, chr17:7592168, C>G, chr2:74690039, G>A,chr12:113448288, A>G, chr17:76130947, G>T, chr2:15674686, T>C,chr2:15607842, T>C, chr14:94847262, T>A, chr4:126412154, G>A,chr22:37271882, T>C, chr20:44640959, G>A, chr17:8138569, C>G,chr12:113357237, G>C, chr12:113357209, G>A, chr11:60893235, C>T,chr12:113357442, G>A, chr5:40964852, A>C, chr14:35497285, T>C,chr19:55494157, G>A, and any combination thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr11:72145307,C>G, chr7:30491421, G>T, chr6:30673403, A>G, chr19:44153248, T>C,chr17:43555253, A>G, chr2:188349523, A>G, chr1:57409459, C>A,chr4:126241248, C>G, chr5:39311336, A>T, chr17:76129619, C>T,chr4:110929301, T>C, chr3:11402163, G>A, chr16:67694044, C>T,chr19:10395141, G>A, chr6:106740989, T>C, chr1:183532364, T>A,chr22:35806756, G>A, chr4:110865044, G>C, chr4:110864533, C>T,chr4:126238090, G>T, chr4:110932508, C>A, chr6:31605016, T>C,chr7:92733766, C>A, chr18:29645930, A>T, and any combination thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr21:45708278,G>A, chr11:108106443, T>A, chr1:57409459, C>A, chr1:196918605, A>G,chr3:58191230, G>T, chr2:230579019, G>A, chr9:137779251, G>A,chr1:27699670, AG>A, chr1:92946625, G>C, chr1:42047208, C>G,chr2:163136505, C>G, chr22:23915583, T>C, chr22:23915745, G>A,chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A,chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A,chr6:51798908, C>T, chr16:81942175, A>G, chr19:8564523, T>G,chr14:94847262, T>A, chr19:7712287, G>C, chr6:32814942, C>T,chr6:32816772, C>A and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr22:23915745,G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr9:137779251, G>A,chr22:23915583, T>C, chr22:35806756, G>A and chr2:163136505, C>G. Insome embodiments, the one or more genetic variations comprise a geneticvariation selected from the group consisting of chr19:8564523, T>G,chr11:108106443, T>A, chr6:32816772, C>A, chr6:32814942, C>T,chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A,chr14:94847262, T>A and chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr22:23915745,G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr19:8564523, T>G,chr11:108106443, T>A, chr9:137779251, G>A, chr22:23915583, T>C,chr22:35806756, G>A, chr2:163136505, C>G, chr6:32816772, C>A,chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A,chr2:230579019, G>A, chr14:94847262 and T>A, chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,chr1:57409459, C>A, chr3:58191230, G>T and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr19:8564523,T>G, chr1:42047208, C>G and chr11:67818269, G>A

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,chr19:8564523, T>G, chr1:57409459, C>A, chr3:58191230, G>T,chr16:81942175, A>G, chr1:42047208, C>G and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:51798908,C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,chr9:137779251, G>A, chr19:7712287, G>C and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:32816772,C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C,chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:51798908,C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,chr9:137779251, G>A, chr19:7712287, G>C, chr16:81942175, A>G,chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C,chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,chr11:67818269, G>A and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr19:48643270,C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,chr11:67818269, G>A, chr16:81942175, A>G, chr19:48643270, C>T,chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr2:163136505, C>G.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr22:23915745, G>A.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr16:81942175, A>G.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr19:7712287, G>C.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr11:67818269, G>A.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr2:163136505, C>G; chr22:23915745, G>A;chr16:81942175, A>G; chr19:7712287, G>C; and chr11:67818269, G>A.

In some embodiments, the SNV is a heterozygous SNV.

In some embodiments, the SNV is a homozygous SNV.

In some embodiments, the one or more genetic variations comprise a pairof single nucleotide variations (SNVs), wherein the pair of SNVs areencoded by any one of SEQ ID NO pairs: 1003 and 1004, 1003 and 1005,1006 and 1007, 1024 and 1025, 1030 and 1031, 1047 and 1048, 1049 and1050, 1063 and 1064, 1063 and 1065, 1063 and 1066, 1075 and 1076, 1091and 1093, 1091 and 1096, 1093 and 1095, 1094 and 1097, 1098 and 1099,1098 and 1100, 1099 and 1100, 1102 and 1103, 1104 and 1106, 1104 and1107, 1104 and 1108, 1104 and 1109, 1104 and 1110, 1104 and 1111, 1104and 1112, 1110 and 1111, 1112 and 1113, 1119 and 1120, 1124 and 1125,1124 and 1126, 1125 and 1126, 1140 and 1141, 1142 and 1144, 1146 and1151, 1147 and 1148, 1147 and 1149, 1153 and 1146, 1153 and 1147, 1155and 1156, 1160 and 1161, 1165 and 1166, 1186 and 1187, 1188 and 1193,1189 and 1193, 1191 and 1192, 1191 and 1193, 1191 and 1195, 1192 and1193, 1192 and 1195, 1196 and 1197, 1206 and 1207, 1210 and 1218, 1211and 1213, 1212 and 1213, 1213 and 1215, 1213 and 1216, 1213 and 1217,1233 and 1238, 1242 and 1243, 1245 and 1246, 1263 and 1260, 1269 and1279, 1270 and 1279, 1270 and 1282, 1271 and 1279, 1274 and 1279, 1278and 1279, 1278 and 1281, 1279 and 1280, 1279 and 1281, 1279 and 1282,1292 and 1293, 1296 and 1297, 1305 and 1314, 1306 and 1310, 1313 and1321 or 1315 and 1322 (see Table 9 or Tables 9 and 7 for a subset), orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto any one of SEQ ID NOs 157, 2, 140, 65, 26, 14 or 45 (see Tables 7 and8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto any one of SEQ ID NOs 2, 140, 65, 26, 14 or 45 (see Table 7), orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NO 157 (see Table 8), or a complement thereof.

In some embodiments, the one or more genetic variations comprise aCNV-SNV pair comprising a CNV and a single nucleotide variation (SNV),wherein the SNV of the CNV-SNV pair is encoded by any one of SEQ ID NOpairs: 146 and 1301, 85 and 1173, 58 and 1107, 58 and 1104, 91 and 1199,103 and 1225, 103 and 1086 or 41 and 1223 (see Tables 1 and 10), orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of: chr8:145154222G>A, chr2:163136505 C>G, chr16:81942175 A>G, chr8:61654298 T>A, andcombinations thereof (see Tables 14 and 16).

In some embodiments, the one or more genetic variations disrupt ormodulate one or more of the following genes: PLCG2, POLE, LRBA, EPG5 andSHARPIN (see Table 17).

In some embodiments, the one or more genetic variations disrupt ormodulate one or more of the following genes: PLCG2, CHD7, IFIH1, AP3B1,EPG5, PIK3CD, LRBA and SHARPIN (see Table 18).

In some embodiments, the corresponding gene encodes a transcript with asequence that has at least 60%, at least 70%, at least 80%, at least90%, at least 95%, or at least 99% sequence identity to any one of SEQID NOs 173-455 or 1500-2177 (see Tables 4 and 12), 2204-2215, 2300-2893,or complements thereof.

In some embodiments, the corresponding gene encodes a transcript with asequence that has at least 60%, at least 70%, at least 80%, at least90%, at least 95%, or at least 99% sequence identity to any one of SEQID NOs 173-455 (see Table 4), or complements thereof.

In some embodiments, the corresponding gene encodes a transcript with asequence that has at least 60%, at least 70%, at least 80%, at least90%, at least 95%, or at least 99% sequence identity to any one of SEQID NOs 1500-2177 (see Table 12), or complements thereof.

In some embodiments, the corresponding gene encodes a transcript with asequence that has at least 60%, at least 70%, at least 80%, at least90%, at least 95%, or at least 99% sequence identity to any one of SEQID NOs 2204-2215, or complements thereof.

In some embodiments, the corresponding gene encodes a transcript with asequence that has at least 60%, at least 70%, at least 80%, at least90%, at least 95%, or at least 99% sequence identity to any one of SEQID NOs 2300-2893, or complements thereof.

In some embodiments, the one or more genetic variations comprise 2 or 3or 4 or 5 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 10 ormore genetic variations.

In some embodiments, the one or more genetic variations comprise 20 ormore genetic variations.

In some embodiments, the one or more genetic variations comprise 50 ormore genetic variations.

In some embodiments, the genetic test or the testing comprisesmicroarray analysis, PCR, sequencing, nucleic acid hybridization, or anycombination thereof.

In some embodiments, the genetic test or the testing comprisesmicroarray analysis selected from the group consisting of a ComparativeGenomic Hybridization (CGH) array analysis and an SNP array analysis.

In some embodiments, the genetic test or the testing comprisessequencing, wherein the sequencing is selected from the group consistingof Massively Parallel Signature Sequencing (MPSS), polony sequencing,454 pyrosequencing, Illumina sequencing, Illumina (Solexa) sequencingusing 10× Genomics library preparation, SOLiD sequencing, ionsemiconductor sequencing, DNA nanoball sequencing, heliscope singlemolecule sequencing, single molecule real time (SMRT) sequencing, RNAPsequencing, Nanopore DNA sequencing, sequencing by hybridization, andmicrofluidic Sanger sequencing.

In some embodiments, the genetic test or the testing comprises analyzinga whole genome of the subject.

In some embodiments, the genetic test or the testing comprises analyzinga whole exome of the subject.

In some embodiments, the genetic test or the testing comprises analyzingnucleic acid information that has already been obtained for a wholegenome or a whole exome of the subject.

In some embodiments, the nucleic acid information is obtained from artin silico analysis.

In some embodiments, the subject is a human subject.

In some embodiments, the polynucleic acid sample comprises a polynucleicacid from blood, saliva, urine, serum, tears, skin, tissue, or hair ofthe subject.

In some embodiments, the method further comprises treating the subjectwith an agent that reduces a viral load in the subject.

In some embodiments, the immunosuppressive agent is administered afterthe viral load is reduced.

In some embodiments, the viral load is a JCV viral load.

In some embodiments, the agent that reduces the viral load is an agentthat targets JCV.

In some embodiments, the method further comprises analyzing for apresence of JCV in a biological sample from the subject. In someembodiments, the method comprises a JCV-antibody test. In someembodiments, the JCV-antibody test has a negative result. In someembodiments, the JCV-antibody test does not detect a presence of JCV inthe biological sample from the subject. In some embodiments, theJCV-antibody test detects a presence of JCV in the biological samplefrom the subject.

In some embodiments, the analyzing for a presence of JCV comprisescontacting a JCV detection reagent to the biological sample.

In some embodiments, the JCV detection reagent is selected from thegroup consisting of an anti-JCV antibody, a JCV specific primer, andcombinations thereof.

Provided herein is a method of treating a condition in a subject in needthereof, comprising: administering a therapeutically effective amount ofone or more immunosuppressive medications to the subject, and one ormore agents that reduce a viral load in the subject, wherein the subjectis identified as not having a risk of developing progressive multifocalleukoencephalopathy (PML) by a genetic test. In some embodiments, thesubject is identified as not having a high risk of developingprogressive multifocal leukoencephalopathy (PML) by a genetic test.

Provided herein is a method of treating a condition in a subject in needthereof, comprising: analyzing a polynucleic acid sample from thesubject for one or more genetic variations that disrupt or modulate agene of GN1-GN765, wherein a genetic variation of the one or moregenetic variations that disrupt or modulate a gene of GN1-GN765 is notpresent in the polynucleic acid sample; identifying the subject as nothaving a risk of developing PML; administering a therapeuticallyeffective amount of one or more immunosuppressive medications to thesubject. In some embodiments, the method comprises identifying thesubject as not having a high risk of developing PML.

Provided herein is a method of identifying a subject as having a risk ofdeveloping PML, comprising: analyzing a polynucleic acid sample from thesubject for one or more genetic variations that disrupt or modulate agene of GN1-GN765, wherein a genetic variation of the one or moregenetic variations that disrupt or modulate a gene of GN1-GN765 is notpresent in the polynucleic acid sample; identifying the subject as nothaving a risk of developing PML. In some embodiments, the methodcomprises identifying the subject as not having a high risk ofdeveloping PML.

Provided herein is a method of identifying a subject as having a risk ofdeveloping progressive multifocal leukoencephalopathy (PML) comprisingobtaining a genetic test result from a polynucleic acid sample from asubject, and identifying the subject as having a risk of developing PMLbased on the genetic test result; wherein the subject isimmunosuppressed.

Provided herein is a method of monitoring a subject as having a risk ofdeveloping progressive multifocal leukoencephalopathy (PML) comprisingobtaining a genetic test result from a polynucleic acid sample from asubject, and identifying the subject as having an increased risk ofdeveloping PML based on the genetic test result; wherein the subject isimmunosuppressed.

In some embodiments, the subject is on an immunosuppressive therapy.

Provided herein is a method of identifying a subject as having a risk ofdeveloping progressive multifocal leukoencephalopathy (PML) comprisingdetecting one or more genetic variations that disrupt or modulate a geneof GN1-GN765 in a polynucleic acid sample from a subject, andidentifying the subject as having a risk of developing PML; wherein thesubject is immunosuppressed.

Provided herein is a method of identifying a subject as having a risk ofdeveloping progressive multifocal leukoencephalopathy (PML) comprising:analyzing a polynucleic acid sample from the subject for one or moregenetic variations that disrupt or modulate a gene of GN1-GN765, whereina genetic variation of the one or more genetic variations that disruptor modulate a gene of GN1-GN765 is present in the polynucleic acidsample; identifying the subject as having a risk of developing PML;wherein the subject is immunosuppressed. In some embodiments, the methodcomprises identifying the subject as having a high risk of developingPML.

In some embodiments, the method comprises not administering atherapeutically effective amount of one or more immunosuppressivemedications to the subject identified as having a risk of developingPML.

In some embodiments, the method comprises analyzing for a presence ofJCV in a biological sample from the subject. In some embodiments, theanalyzing for a presence of JCV comprises a JCV-antibody test, a CD62Ltest, or a CSF IgM oligoclonal bands test. In some embodiments, theanalyzing for a presence of JCV is performed prior to the genetic test.In some embodiments, the analyzing for a presence of JCV is performedafter the genetic test. In some embodiments, the analyzing for apresence of JCV is performed concurrently with the genetic test. In someembodiments, the analyzing for a presence of JCV identifies the subjectas having JCV. In some embodiments, the analyzing for a presence of JCVidentifies the subject as not having JCV. In some embodiments, thegenetic test result identifies the subject as having a risk or anincreased risk of developing PML. In some embodiments, the genetic testresult identifies the subject as not having a risk or not having anincreased risk of developing PML.

In some embodiments, the subject is immunosuppressed. In someembodiments, the subject has HIV. In some embodiments, the subject hasHIV infection. In some embodiments, the subject is at risk of HIVinfection. In some embodiments, the method comprises administering atherapeutically effective amount of one or more antiviral drugs, such asprotease inhibitors (lopinavir/ritonavir {e.g., KALETRA}, indinavir{e.g., CRIXIVAN}, ritonavir {e.g., NORVIR}, nelfinavir {e.g., VIRACEPT},saquinavir hard gel capsules {e.g., INVIRASE}, atazanavir {e.g.,REYATAZ}, amprenavir {e.g., AGENERASE}, fosamprenavir {e.g., TELZIR},tipranavir{e.g., APTIVUS}), reverse transcriptase inhibitors, includingnon-nucleoside and nucleoside/nucleotide inhibitors (AZT {zidovudine,e.g., Retrovir}, ddI {didanosine, e.g., VIDEX}, 3TC {lamivudine, e.g.,EPIVIR}, d4T {stavudine, e.g., ZERIT}, abacavir {e.g., ZIAGEN}, FTC{emtricitabine, e.g., EMTRIVA}, tenofovir {e.g., VIREAD}, efavirenz{e.g., SUSTIVA} and nevirapine {e.g., VIRAMUNE}), fusion inhibitors T20{enfuvirtide, e.g., FUZEON}, integrase inhibitors (Raltegravir, e.g.,ISENTRESS, MK-0518; and elvitegravir, e.g., VITEKTA, GS-9137), andmaturation inhibitors (bevirimat {PA-457}).

In some embodiments, the condition is a cancer, a hematologicmalignancy, an organ transplant, or an autoimmune disease. In someembodiments, the condition is idiopathic CD4+ lymphocytopenia (ICL).

In some embodiments, the condition is an autoimmune disease.

In some embodiments, the autoimmune disease is selected from the groupconsisting of Addison disease, Behcet's Disease, Inflammatory boweldisease, Celiac disease-sprue (gluten-sensitive enteropathy), Crohn'sdisease, Dermatomyositis, Focal segmental glomerulosclerosis, Gravesdisease, Hashimoto thyroiditis, Multiple sclerosis, Myasthenia gravis,Pemphigus, Pemphigoid, Aplastic anemia, Pernicious anemia, Autoimmunehemolytic anemia, Erythroblastopenia, Thrombocytopenic purpura, Evanssyndrome, Vasculitis, Granulomatosis with polyangiitis, Chronicinflammatory demyelinating polyneuropathy, Guillain-Barre syndrome,Anti-NMDA receptor encephalitis, Devic's disease, Autoimmunepancreatitis, Opsoclonus myoclonus syndrome, IgG4-related disease,Psoriasis, Reactive arthritis, Rheumatoid arthritis, Juvenile idiopathicarthritis, Sarcoidosis, Sjögren syndrome, Systemic lupus erythematosus,Type I diabetes, Vitiligo, or Ulcerative colitis.

In some embodiments, the autoimmune disease is multiple sclerosis orCrohn's disease.

In some embodiments, the one or more immunosuppressive medicationscomprise a glucocorticoid, cytostatic, antibody, drug acting onimmunophilins, interferon, opioid, TNF binding protein, mycophenolate,small biological agent, small molecule, organic compound, or anycombination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic(AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4,anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent,anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb,anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctionalfusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 andanti-LAG3 mAb, CDId ligand, CD40 agonist, Complement C5a inhibitor,CSFIR inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor,FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factorreceptor-related gene [GITR] agonist, glutaminase inhibitor, Humanmonoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptortyrosine kinase inhibitor, neutrophil elastase inhibitor, NotchInhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L,ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator,Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combinationthereof.

In some embodiments, the one or more immunosuppressive medicationscomprise abatacept (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab,adrenocorticotropic hormone, agatolimod sodium, AJM300, aldesleukin,alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride,alvocidib, ambrisentan (e.g. LETAIRIS), aminocamptothecin, amiselimod,anakinra, andecaliximab, andrographolides (a botanical medicinal herbalso known as IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib,asparaginase, atacicept, atezolizumab, avelumab, azacitidine,azathioprine, bafetinib, baminercept, baricitinib, basiliximab,becatecarin, begelomab, belatacept, belimumab, bemcentinib,bendamustine, bendamustine (e.g. bendamustine hydrochloride), betalutinwith lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab,binimetinib, bleomycin, blinatumomab, BNZ-1, bortezomib (e.g. VELCADE),brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan,canakinumab, capecitabine, carboplatin, carfilzomib, carmustine,cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab(e.g. certolizumab pegol), cetuximab, chidamide, chlorambucil, CHS-131,cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab,clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine,cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine (e.g.AMPYRA), daprolizumab pegol, daratumumab, dasatinib, defactinib,defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate,dinaciclib, diroximel fumarate (e.g. VUMERITY), doxorubicin, doxorubicin(e.g. doxorubicin hydrochloride), durvalumab, duvelisib, duvortuxizumab,eculizumab (e.g. SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (aneuropeptide combination of metenkefalin and tridecactide), elezanumab,elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g. FUZEON),entinostat, entospletinib, enzastaurin, epacadostat, epirubicin,epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumnab,everolimus, evobrutinib, filgotinib, fingolimod (e.g. fingolimodhydrochloride), firategrast, fludarabine, fluorouracil, fontolizumab,forodesine hydrochloride, fostamatinib, galunisertib, ganetespib,ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib,glassia, glatiramer acetate, glembatumumab vedotin, glesatinib,golimumab (e.g. SIMPONI), guadecitabine, hydrocortisone,hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan,ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide,iguratimod, imatinib, imexon, IMU-838, infliximab, inotuzumabozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b,interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib,itacitinib, ixazomib, lapatinib, laquinimod, laromustine,ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole (e.g.FEMARA), levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib,lumiliximab, maraviroc (e.g. SELZENTRY), masitinib, mavrilimumab,melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone,milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab,mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox,muromonab-CD3, mycophenolate mofetil (e.g. mycophenolate mofetilhydrochloride), mycophenolic acid, namilumab, natalizumab, navitoclax,neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclaxmesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab,olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab,oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib,palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim (e.g.NEULASTA), peginterferon beta-1a, pegsunercept (peg stnf-ri),pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine,pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex,pixantrone, pleneva, plovamer acetate, polatuzumab vedotin,pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide,R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant il-12,relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir (e.g.NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246, sarilumab,secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod(e.g. MAYZENT), sirolimus (rapamycin), sirukumab, sitravatinib,sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenonepigallocatechin-gallate, tabalumab, tacrolimus (e.g. tacrolimusanhydrous), talabostat mesylate, talacotuzumab, tanespimycin,tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib,terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa,tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab,tofacitinib, TR-14035, tregalizumab, tremelimumab, treosulfan,ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab,varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax,vinblastine, vincristine, vinorelbine ditartrate, visilizumab,vismodegib, vistusertib, voriconazole (e.g. VFEND), vorinostat,vosaroxin, ziv-aflibercept, or any combination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise 2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoicacid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501,ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555,ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452,Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884,AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803,ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APLA12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797,ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASN002, ASP015K,ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188,ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991,AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312,BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100,BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492,BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, BIBR 796BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564,BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205,BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061,BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088,CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323,CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116,CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131,CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102,CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP,DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555,DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIAl1, EOC202,ETBX-011, F8IL10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327,FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853,GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L,GS-1101, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249,GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781,GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769,GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286,HL2351, HL237, hLL1-DOX (IMMU-115), HLXO1, HM71224, HMPL-523, HSC835,HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125,INCAGNO2385, INCB018424, INCB028050, INCB039110, INCB047986,INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056,ISF35, ISIS 104838, ITF2357, JCARH125, JHIL1011, JNJ 38518168,JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011,KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525,LAM-002A, LBECO101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399,LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367,LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013,MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538,MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280,MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812,MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibodyM-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022,MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303,MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071,NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012,NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNC0215-0384,NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON0910Na,ONO-2506PO, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05,PBF-509, PBR06, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001,PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586,PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600,PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326,PRO131921, PR0283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001,RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077,RGB-03, RGI-2001, RHB-104, RNS60, R05045337, R07123520, Rob 803,RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323,SB683699, SBI-087, SC12267 (4SC-101), SCH 727965, SCIO-469, SD-101,SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136,SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996,SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023,SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901,TGR-1202, TH-302, TLO11, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015,TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R,VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844,XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365, or anycombination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab, diroximel fumarate, siponimod or any combination thereof

In some embodiments, the one or more immunosuppressive medicationscomprise natalizumab (e.g., TYSABRI).

In some embodiments, the one or more genetic variations comprise a pointmutation, polymorphism, single nucleotide polymorphisms (SNP), singlenucleotide variation (SNV), translocation, insertion, deletion,amplification, inversion, interstitial deletion, copy number variation(CNV), structural variation (SV), loss of heterozygosity, or anycombination thereof.

In some embodiments, the one or more genetic variations result in a lossof function of the corresponding gene.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN1-GN490.

In some embodiments, the gene comprises a gene selected from the groupconsisting of gene numbers (GNs) 1-156 (in Table 3).

In some embodiments, the gene comprises a gene selected from the groupconsisting of gene numbers (GNs) in Table 6.

In some embodiments, the gene comprises a gene selected from the groupconsisting of gene numbers (GNs) GN491-GN492 in Table 29.

In some embodiments, the gene comprises a gene selected from the groupconsisting of gene numbers (GNs) GN493-GN762 in Table 31.

In some embodiments, the gene comprises a gene selected from the groupconsisting of gene numbers (GNs) GN763-GN765 in Table 48.

In some embodiments, the corresponding gene comprises a gene selectedfrom Tables 34-40, 42, 45A, 45B, 45C, 48, 50A, 50B and 51-62.

In some embodiments, the gene comprises a gene selected from the groupconsisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1,POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A,PIK3CD, PNP, MCEE, DOCK2 and ALG12 (see Table 13).

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1,JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1,TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2, ALG12, FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER,FCN2, FCN3, GFI1, HIVEP3, IFIH1, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1,NQO2, PKHD1, PLCG2, PRAM1, SERPINA1, STXBP2, TAP1 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER,FCN2, FCN3, GFI1, HIVEP3, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1, NQO2,PKHD1, PRAM1, SERPINA1, and TAP1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of IGLL1, MDC1, STXBP2, FCN2, IGLL1, MCM5 andIFIH1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PRAM1, ATM, TAP1, PLCG2, FCN3, DNER,SERPINA1 and LRBA.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of IGLL1, MDC1, STXBP2, PRAM1, ATM, FCN2,IGLL1, MCM5, IFIH1, TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LY9, LIG1, PKHD1, AIRE, GFIL, CFHR2, NQO2,C8B, DNASE1L3 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PRAM1, HIVEP3 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LY9, LIG1, PKHD1, AIRE, GFI1, CFHR2, NQO2,PRAM1, C8B, DNASE1L3, PLCG2, HIVEP3 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, IGLL1,TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3,SERPINA1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, TCIRG1, ATM,MDC1, PRAM1, FCN2, STXBP2, PLCG2, TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3and SERPINA1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LY9, PKHD1, AIRE, CFHR2, NQO2, IGLL1,PRAM1, MDC1, FCN2, STXBP2, TCIRG1 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of LIG1, MCM5, GFI1, IFIH1, IGLL1, ATM, TAP1,FCN3, LRBA and SERPINA1.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a sequence with at least 60%, at least 70%,at least 80%, at least 90%, at least 95%, or at least 99% sequenceidentity to SEQ ID NOs 1-172 or SRN1-SRN363, with 100% sequence identityto SEQ ID NOs 1000-1329, or with at least 80% and less than 100%sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by asequence with at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203, orSRN364-SRN366, with 100% sequence identity to SEQ ID NOs 3000-3274, orwith at least 80% and less than 100% sequence identity to GN491-GN765,or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NOs 1-172, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NOs 2200-2203, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV sub-region (SRN) with at least 60%,at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%sequence identity to SRN1-SRN363, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV sub-region (SRN) with at least 60%,at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%sequence identity to SRN364-SRN366, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by asingle nucleotide variation (SNV) with a sequence of any one of SEQ IDNOs: 1000-1329, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NOs: 3000-3274, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a sequence with at least 80% and less than100% sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a sequence with at least 80% and less than100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1011,1012, 1014, 1016, 1017, 1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036,1037, 1040, 1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062,1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076, 1077, 1078,1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1101, 1104, 1107, 1114,1116, 1118, 1121, 1122, 1123, 1125, 1126, 1127, 1128, 1129, 1130, 1131,1133, 1135, 1136, 1137, 1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154,1157, 1160, 1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176,1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200, 1201,1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226, 1227, 1228, 1229,1230, 1231, 1232, 1235, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254,1255, 1256, 1259, 1260, 1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279,1283, 1284, 1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311,1327 or 1328 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035,1036, 1040, 1056, 1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127,1135, 1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184, 1193,1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255, 1256, 1259, 1260,1261, 1263, 1273, 1278, 1279, 1284, 1287, 1289, 1299 or 1311 (see Table7), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012,1014, 1016, 1017, 1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058,1059, 1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076, 1078,1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104, 1107, 1116, 1118,1121, 1122, 1128, 1129, 1130, 1131, 1133, 1136, 1137, 1138, 1146, 1147,1150, 1152, 1160, 1161, 1165, 1166, 1168, 1169, 1171, 1175, 1176, 1177,1178, 1179, 1180, 1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220,1226, 1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250, 1251,1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286, 1290, 1291, 1300,1301, 1304, 1327 or 1328 (see Table 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr16:81942175A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T,chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,chr1:182554557 C>T, chr8:145154824 A>C, chr20:62305450 C>T,chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A,chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T,chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T,chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A,chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T,chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A,chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T,chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof(see Tables 14 and 15).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr16:81942175A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T,chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,chr1:182554557 C>T, and any combination thereof (see Table 14).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr8:145154824A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G,chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T,chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T,chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C,chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T,chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and anycombination thereof (see Table 15).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:196759282,C>T, chr4:126412634, C>G, chr10:75673748, A>C, chr6:30675830, T>A,chr6:30680721, G>A, chr12:56385915, GGGA>G, chr18:57103126, G>A,chr3:171321023, C>T, chr1:59131311, G>T, chr22:31008867, T>C,chr2:74690378, C>T, chr7:7592168, C>G, chr2:74690039, G>A,chr12:113448288, A>G, chr17:76130947, G>T, chr2:15674686, T>C,chr2:15607842, T>C, chr14:94847262, T>A, chr4:126412154, G>A,chr22:37271882, T>C, chr20:44640959, G>A, chr17:8138569, C>G,chr12:113357237, G>C, chr12:113357209, G>A, chr11:60893235, C>T,chr12:113357442, G>A, chr5:40964852, A>C, chr14:35497285, T>C,chr19:55494157, G>A, and any combination thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr11:72145307,C>G, chr7:30491421, G>T, chr6:30673403, A>G, chr19:44153248, T>C,chr17:43555253, A>G, chr2:188349523, A>G, chr1:57409459, C>A,chr4:126241248, C>G, chr5:39311336, A>T, chr17:76129619, C>T,chr4:110929301, T>C, chr3:11402163, G>A, chr16:67694044, C>T,chr19:10395141, G>A, chr6:106740989, T>C, chr1:183532364, T>A,chr22:35806756, G>A, chr4:110865044, G>C, chr4:110864533, C>T,chr4:126238090, G>T, chr4:110932508, C>A, chr6:31605016, T>C,chr7:92733766, C>A, chr18:29645930, A>T, and any combination thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr21:45708278,G>A, chr11:108106443, T>A, chr1:57409459, C>A, chr1:196918605, A>G,chr3:58191230, G>T, chr2:230579019, G>A, chr9:137779251, G>A,chr1:27699670, AG>A, chr1:92946625, G>C, chr1:42047208, C>G,chr2:163136505, C>G, chr22:23915583, T>C, chr22:23915745, G>A,chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A,chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A,chr6:51798908, C>T, chr16:81942175, A>G, chr19:8564523, T>G,chr14:94847262, T>A, chr19:7712287, G>C, chr6:32814942, C>T,chr6:32816772, C>A and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr22:23915745,G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr9:137779251, G>A,chr22:23915583, T>C, chr22:35806756, G>A and chr2:163136505, C>G. Insome embodiments, the one or more genetic variations comprise a geneticvariation selected from the group consisting of chr19:8564523, T>G,chr11:108106443, T>A, chr6:32816772, C>A, chr6:32814942, C>T,chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A,chr14:94847262, T>A and chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr22:23915745,G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr19:8564523, T>G,chr11:108106443, T>A, chr9:137779251, G>A, chr22:23915583, T>C,chr22:35806756, G>A, chr2:163136505, C>G, chr6:32816772, C>A,chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A,chr2:230579019, G>A, chr14:94847262 and T>A, chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,chr1:57409459, C>A, chr3:58191230, G>T and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr19:8564523,T>G, chr1:42047208, C>G and chr11:67818269, G>A

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,chr19:8564523, T>G, chr1:57409459, C>A, chr3:58191230, G>T,chr16:81942175, A>G, chr1:42047208, C>G and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:51798908,C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,chr9:137779251, G>A, chr19:7712287, G>C and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:32816772,C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C,chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:51798908,C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,chr9:137779251, G>A, chr19:7712287, G>C, chr16:81942175, A>G,chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C,chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,chr11:67818269, G>A and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr19:48643270,C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,chr11:67818269, G>A, chr16:81942175, A>G, chr19:48643270, C>T,chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr2:163136505, C>G.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr22:23915745, G>A.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr16:81942175, A>G.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr19:7712287, G>C.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr11:67818269, G>A.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr2:163136505, C>G; chr22:23915745, G>A;chr16:81942175, A>G; chr19:7712287, G>C; and chr11:67818269, G>A.

In some embodiments, the SNV is a heterozygous SNV.

In some embodiments, the SNV is a homozygous SNV.

In some embodiments, the one or more genetic variations comprise a pairof single nucleotide variations (SNVs), wherein the pair of SNVs areencoded by any one of SEQ ID NO pairs: 1003 and 1004, 1003 and 1005,1006 and 1007, 1024 and 1025, 1030 and 1031, 1047 and 1048, 1049 and1050, 1063 and 1064, 1063 and 1065, 1063 and 1066, 1075 and 1076, 1091and 1093, 1091 and 1096, 1093 and 1095, 1094 and 1097, 1098 and 1099,1098 and 1100, 1099 and 1100, 1102 and 1103, 1104 and 1106, 1104 and1107, 1104 and 1108, 1104 and 1109, 1104 and 1110, 1104 and 1111, 1104and 1112, 1110 and 1111, 1112 and 1113, 1119 and 1120, 1124 and 1125,1124 and 1126, 1125 and 1126, 1140 and 1141, 1142 and 1144, 1146 and1151, 1147 and 1148, 1147 and 1149, 1153 and 1146, 1153 and 1147, 1155and 1156, 1160 and 1161, 1165 and 1166, 1186 and 1187, 1188 and 1193,1189 and 1193, 1191 and 1192, 1191 and 1193, 1191 and 1195, 1192 and1193, 1192 and 1195, 1196 and 1197, 1206 and 1207, 1210 and 1218, 1211and 1213, 1212 and 1213, 1213 and 1215, 1213 and 1216, 1213 and 1217,1233 and 1238, 1242 and 1243, 1245 and 1246, 1263 and 1260, 1269 and1279, 1270 and 1279, 1270 and 1282, 1271 and 1279, 1274 and 1279, 1278and 1279, 1278 and 1281, 1279 and 1280, 1279 and 1281, 1279 and 1282,1292 and 1293, 1296 and 1297, 1305 and 1314, 1306 and 1310, 1313 and1321 or 1315 and 1322 (see Table 9 or Tables 9 and 7 for a subset), orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto any one of SEQ ID NOs 157, 2, 140, 65, 26, 14 or 45 (see Tables 7 and8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto any one of SEQ ID NOs 2, 140, 65, 26, 14 or 45 (see Table 7), orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NO 157 (see Table 8), or a complement thereof.

In some embodiments, the one or more genetic variations comprise aCNV-SNV pair comprising a CNV and a single nucleotide variation (SNV),wherein the SNV of the CNV-SNV pair is encoded by any one of SEQ ID NOs1301, 1173, 1107, 1104, 1199, 1225, 1086 or 1223 (see Table 10), orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of one or more ofthe following: chr8:145154222 G>A, chr2:163136505 C>G, chr16:81942175A>G, and chr8:61654298 T>A (see Tables 14 and 16).

In some embodiments, the one or more genetic variations disrupt ormodulate one or more of the following genes: PLCG2, POLE, LRBA, EPG5 andSHARPIN (see Table 17).

In some embodiments, the one or more genetic variations disrupt ormodulate one or more of the following genes: PLCG2, CHD7, IFIH1, AP3B1,EPG5, PIK3CD, LRBA and SHARPIN (see Table 18).

In some embodiments, the gene encodes a transcript with a sequence thathas at least 60%, at least 70%, at least 80%, at least 90%, at least95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455or 1500-2177 (see Tables 4 and 12), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence thathas at least 60%, at least 70%, at least 80%, at least 90%, at least95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455(see Table 4), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence thathas at least 60%, at least 70%, at least 80%, at least 90%, at least95%, or at least 99% sequence identity to any one of SEQ ID NOs1500-2177 (see Table 12), or complements thereof.

In some embodiments, the one or more genetic variations comprise 2 or 3or 4 or 5 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 10 ormore genetic variations.

In some embodiments, the one or more genetic variations comprise 20 ormore genetic variations.

In some embodiments, the one or more genetic variations comprise 50 ormore genetic variations.

In some embodiments, the analyzing comprises microarray analysis, PCR,sequencing, nucleic acid hybridization, or any combination thereof.

In some embodiments, the genetic test result comprises a genetic testresult from a microarray analysis, PCR, sequencing, nucleic acidhybridization, or any combination thereof.

In some embodiments, the detecting comprises a microarray analysis, PCR,sequencing, nucleic acid hybridization, or any combination thereof.

In some embodiments, the microarray analysis selected from the groupconsisting of a Comparative Genomic Hybridization (CGH) array analysisand an SNP array analysis.

In some embodiments, the sequencing is selected from the groupconsisting of Massively Parallel Signature Sequencing (MPSS), polonysequencing, 454 pyrosequencing, Illumina sequencing, Illumina (Solexa)sequencing using 10× Genomics library preparation, SOLiD sequencing, ionsemiconductor sequencing, DNA nanoball sequencing, heliscope singlemolecule sequencing, single molecule real time (SMRT) sequencing, RNAPsequencing, Nanopore DNA sequencing, sequencing by hybridization, andmicrofluidic Sanger sequencing.

In some embodiments, the analyzing comprises analyzing a whole genome ofthe subject.

In some embodiments, the analyzing comprises analyzing a whole exome ofthe subject.

In some embodiments, the analyzing comprises analyzing nucleic acidinformation that has already been obtained for a whole genome or a wholeexome of the subject.

In some embodiments, the nucleic acid information is obtained from an insilico analysis.

In some embodiments, the subject is a human subject.

In some embodiments, the polynucleic acid sample comprises a polynucleicacid from blood, saliva, urine, serum, tears, skin, tissue, or hair ofthe subject.

In some embodiments, the method further comprises analyzing for apresence of JCV in a biological sample from the subject.

In some embodiments, the analyzing for a presence of JCV comprisescontacting a JCV detection reagent to the biological sample.

In some embodiments, the JCV detection reagent is selected from thegroup consisting of an anti-JCV antibody, a JCV specific primer, andcombinations thereof.

Provided herein is a kit, comprising reagents for assaying a polynucleicacid sample from a subject in need thereof for the presence of one ormore genetic variations that disrupt or modulate a gene of GN1-GN490.

In some embodiments, the reagents comprise at least one contiguousoligonucleotide that hybridizes to a fragment of the polynucleic acidsample.

In some embodiments, the reagents comprise at least one pair ofoligonucleotides that hybridize to opposite strands of a fragment of thepolynucleic acid sample.

In some embodiments, the kit further comprises one or moreimmunosuppressive medications.

In some embodiments, the one or more immunosuppressive medicationscomprise a glucocorticoid, cytostatic, antibody, drug acting onimmunophilins, interferon, opioid, TNF binding protein, mycophenolate,small biological agent, or any combination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise an interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab, siponimod or any combination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise natalizumab (e.g., TYSABRI).

In some embodiments, the kit further comprises a JCV detection reagent.

In some embodiments, the JCV detection reagent is selected from thegroup consisting of an anti-JCV antibody, a JCV specific primer, andcombinations thereof.

In some embodiments, the kit further comprises a set of instructions foradministration of the one or more immunosuppressive medications.

In some embodiments, the one or more genetic variations comprise a pointmutation, polymorphism, single nucleotide polymorphisms (SNP), singlenucleotide variation (SNV), translocation, insertion, deletion,amplification, inversion, interstitial deletion, copy number variation(CNV), structural variation (SV), loss of heterozygosity, or anycombination thereof.

In some embodiments, the one or more genetic variations result in a lossof function of the corresponding gene.

In some embodiments, the one or more genetic variations comprise 5 ormore genetic variations.

In some embodiments, the one or more genetic variations comprise 10 ormore genetic variations.

In some embodiments, the one or more genetic variations comprise 20 ormore genetic variations.

In some embodiments, the one or more genetic variations comprise 50 ormore genetic variations.

In some embodiments, the subject is a human subject.

In some embodiments, the polynucleic acid sample comprises a polynucleicacid from blood, saliva, urine, serum, tears, skin, tissue, or hair ofthe subject.

Provided herein is a panel of polynucleic acids for detecting one ormore genetic variations that disrupt or modulate a gene of GN1-GN765,wherein each polynucleic acid of the panel comprises a sequencecomplementary to a sequence of one or more genetic variation orcomplements thereof that disrupts or modulates a gene selected from thegroup consisting of GN1-GN765.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a sequence with at least 60%, at least 70%,at least 80%, at least 90%, at least 95%, or at least 99% sequenceidentity to SEQ ID NOs 1-172, 2200-2203, or SRN1-SRN366, with 100%sequence identity to SEQ ID NOs 1000-1329, 3000-3274, or with at least80% and less than 100% sequence identity to GN1-GN765, or complementsthereof.

In some embodiments, the one or more genetic variations are encoded by asequence with at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203 orSRN364-SRN366, with 100% sequence identity to SEQ ID NOs 3000-3274, orwith at least 80% and less than 100% sequence identity to GN491-GN765,or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NOs 1-172, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NOs 2200-2203, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV sub-region (SRN) with at least 60%,at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%sequence identity to SRN1-SRN363, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV sub-region (SRN) with at least 60%,at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%sequence identity to SRN364-SRN366, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NOs: 1000-1329, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NOs: 3000-3274, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a sequence with at least 80% and less than100% sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a sequence with at least 80% and less than100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1011,1012, 1014, 1016, 1017, 1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036,1037, 1040, 1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062,1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076, 1077, 1078,1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1101, 1104, 1107, 1114,1116, 1118, 1121, 1122, 1123, 1125, 1126, 1127, 1128, 1129, 1130, 1131,1133, 1135, 1136, 1137, 1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154,1157, 1160, 1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176,1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200, 1201,1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226, 1227, 1228, 1229,1230, 1231, 1232, 1235, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254,1255, 1256, 1259, 1260, 1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279,1283, 1284, 1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311,1327 or 1328 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035,1036, 1040, 1056, 1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127,1135, 1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184, 1193,1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255, 1256, 1259, 1260,1261, 1263, 1273, 1278, 1279, 1284, 1287, 1289, 1299 or 1311 (see Table7), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012,1014, 1016, 1017, 1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058,1059, 1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076, 1078,1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104, 1107, 1116, 1118,1121, 1122, 1128, 1129, 1130, 1131, 1133, 1136, 1137, 1138, 1146, 1147,1150, 1152, 1160, 1161, 1165, 1166, 1168, 1169, 1171, 1175, 1176, 1177,1178, 1179, 1180, 1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220,1226, 1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250, 1251,1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286, 1290, 1291, 1300,1301, 1304, 1327 or 1328 (see Table 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a single nucleotide variation (SNV) with asequence of any one of SEQ ID NO: 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr16:81942175A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T,chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,chr1:182554557 C>T, chr8:145154824 A>C, chr20:62305450 C>T,chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A,chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T,chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T,chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A,chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T,chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A,chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T,chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof(see Tables 14 and 15).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr16:81942175A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>190,chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,chr1:182554557 C>T, and any combination thereof (see Table 14).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr8:145154824A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G,chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T,chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T,chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C,chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T,chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and anycombination thereof (see Table 15).

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:196759282,C>T, chr4:126412634, C>G, chr10:75673748, A>C, chr6:30675830, T>A,chr6:30680721, G>A, chr12:56385915, GGGA>G, chr18:57103126, G>A,chr3:171321023, C>T, chr1:59131311, G>T, chr22:31008867, T>C,chr2:74690378, C>T, chr17:7592168, C>G, chr2:74690039, G>A,chr12:113448288, A>G, chr17:76130947, G>T, chr2:15674686, T>C,chr2:15607842, T>C, chr14:94847262, T>A, chr4:126412154, G>A,chr22:37271882, T>C, chr20:44640959, G>A, chr17:8138569, C>G,chr12:113357237, G>C, chr12:113357209, G>A, chr11:60893235, C>T,chr12:113357442, G>A, chr5:40964852, A>C, chr14:35497285, T>C,chr19:55494157, G>A, and any combination thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr11:72145307,C>G, chr7:30491421, G>T, chr6:30673403, A>G, chr19:44153248, T>C,chr17:43555253, A>G, chr2:188349523, A>G, chr1:57409459, C>A,chr4:126241248, C>G, chr5:39311336, A>T, chr17:76129619, C>T,chr4:110929301, T>C, chr3:11402163, G>A, chr16:67694044, C>T,chr19:10395141, G>A, chr6:106740989, T>C, chr1:183532364, T>A,chr22:35806756, G>A, chr4:110865044, G>C, chr4:110864533, C>T,chr4:126238090, G>T, chr4:110932508, C>A, chr6:31605016, T>C,chr7:92733766, C>A, chr18:29645930, A>T, and any combination thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr21:45708278,G>A, chr11:108106443, T>A, chr1:57409459, C>A, chr1:196918605, A>G,chr3:58191230, G>T, chr2:230579019, G>A, chr9:137779251, G>A,chr1:27699670, AG>A, chr1:92946625, G>C, chr1:42047208, C>G,chr2:163136505, C>G, chr22:23915583, T>C, chr22:23915745, G>A,chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A,chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A,chr6:51798908, C>T, chr16:81942175, A>G, chr19:8564523, T>G,chr14:94847262, T>A, chr19:7712287, G>C, chr6:32814942, C>T,chr6:32816772, C>A and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr22:23915745,G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr9:137779251, G>A,chr22:23915583, T>C, chr22:35806756, G>A and chr2:163136505, C>G. Insome embodiments, the one or more genetic variations comprise a geneticvariation selected from the group consisting of chr19:8564523, T>G,chr11:108106443, T>A, chr6:32816772, C>A, chr6:32814942, C>T,chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A,chr14:94847262, T>A and chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr22:23915745,G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr19:8564523, T>G,chr11:108106443, T>A, chr9:137779251, G>A, chr22:23915583, T>C,chr22:35806756, G>A, chr2:163136505, C>G, chr6:32816772, C>A,chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A,chr2:230579019, G>A, chr14:94847262 and T>A, chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,chr1:57409459, C>A, chr3:58191230, G>T and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr19:8564523,T>G, chr1:42047208, C>G and chr11:67818269, G>A

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,chr19:8564523, T>G, chr1:57409459, C>A, chr3:58191230, G>T,chr16:81942175, A>G, chr1:42047208, C>G and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:51798908,C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,chr9:137779251, G>A, chr19:7712287, G>C and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:32816772,C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C,chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr6:51798908,C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,chr9:137779251, G>A, chr19:7712287, G>C, chr16:81942175, A>G,chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C,chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,chr11:67818269, G>A and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr19:48643270,C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of chr1:160769595,AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,chr11:67818269, G>A, chr16:81942175, A>G, chr19:48643270, C>T,chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C andchr14:94847262, T>A.

In some embodiments, the one or more genetic variations compriseschr21:45708278 G>A, chr14:94847262 T>A, chr1:57409459 C>A,chr22:35806756 G>A, chr11:108106443 T>A, chr1:196918605 A>G,chr3:58191230 G>T, chr2:230579019 G>A, chr9:137779251 G>A, chr1:27699670AG>A, chr19:48643270 C>T, chr4:151793903 T>C, chr1:160769595 AG>A,chr6:30673359 T>G, chr6:3015818 G>A, chr19:8564523 T>G, chr6:32814942C>T or chr6:32816772 C>A; wherein chromosome positions of the one ormore genetic variations are defined with respect to UCSC hg19.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr2:163136505, C>G.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr22:23915745, G>A.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr16:81942175, A>G.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr19:7712287, G>C.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr11:67818269, G>A.

In some embodiments, the one or more genetic variations do not comprisea genetic variation of chr2:163136505, C>G; chr22:23915745, G>A;chr16:81942175, A>G; chr19:7712287, G>C; and chr11:67818269, G>A.

In some embodiments, the SNV is a heterozygous SNV.

In some embodiments, the SNV is a homozygous SNV.

In some embodiments, the one or more genetic variations comprise a pairof single nucleotide variations (SNVs), wherein the pair of SNVs areencoded by any one of SEQ ID NO pairs: 1003 and 1004, 1003 and 1005,1006 and 1007, 1024 and 1025, 1030 and 1031, 1047 and 1048, 1049 and1050, 1063 and 1064, 1063 and 1065, 1063 and 1066, 1075 and 1076, 1091and 1093, 1091 and 1096, 1093 and 1095, 1094 and 1097, 1098 and 1099,1098 and 1100, 1099 and 1100, 1102 and 1103, 1104 and 1106, 1104 and1107, 1104 and 1108, 1104 and 1109, 1104 and 1110, 1104 and 1111, 1104and 1112, 1100 and 1111, 1112 and 1113, 1119 and 1120, 1124 and 1125,1124 and 1126, 1125 and 1126, 1140 and 1141, 1142 and 1144, 1146 and1151, 1147 and 1148, 1147 and 1149, 1153 and 1146, 1153 and 1147, 1155and 1156, 1160 and 1161, 1165 and 1166, 1186 and 1187, 1188 and 1193,1189 and 1193, 1191 and 1192, 1191 and 1193, 1191 and 1195, 1192 and1193, 1192 and 1195, 1196 and 1197, 1206 and 1207, 1210 and 1218, 1211and 1213, 1212 and 1213, 1213 and 1215, 1213 and 1216, 1213 and 1217,1233 and 1238, 1242 and 1243, 1245 and 1246, 1263 and 1260, 1269 and1279, 1270 and 1279, 1270 and 1282, 1271 and 1279, 1274 and 1279, 1278and 1279, 1278 and 1281, 1279 and 1280, 1279 and 1281, 1279 and 1282,1292 and 1293, 1296 and 1297, 1305 and 1314, 1306 and 1310, 1313 and1321 or 1315 and 1322 (see Table 9 or Tables 9 and 7 for a subset), orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto any one of SEQ ID NOs 157, 2, 140, 65, 26, 14 or 45 (see Tables 7 and8), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto any one of SEQ ID NOs 2, 140, 65, 26, 14 or 45 (see Table 7), orcomplements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation encoded by a CNV with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or at least 99% sequence identityto SEQ ID NO 157 (see Table 8), or a complement thereof

In some embodiments, the one or more genetic variations comprise a CNVand a single nucleotide variations (SNV), wherein SNVs is encoded by anyone of SEQ ID NOs 1301, 1173, 1107, 1104, 1199, 1225, 1086 or 1223 (seeTable 10), or complements thereof.

In some embodiments, the one or more genetic variations comprise agenetic variation selected from the group consisting of one or more ofthe following: chr8:145154222 G>A, chr2:163136505 C>G, chr16:81942175A>G, and chr8:61654298 T>A (see Tables 14 and 16).

In some embodiments, the one or more genetic variations disrupt ormodulate one or more of the following genes: PLCG2, POLE, LRBA, EPG5 andSHARPIN (see Table 17).

In some embodiments, the one or more genetic variations disrupt ormodulate one or more of the following genes: PLCG2, CHD7, IFIH1, AP3B1,EPG5, PIK3CD, LRBA and SHARPIN (see Table 18).

In some embodiments, the gene encodes a transcript with a sequence thathas at least 60%, at least 70%, at least 80%, at least 90%, at least95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455,1500-2177, 2204-2215, 2300-2893 (see Tables 4, 12, 30, and 32), orcomplements thereof.

In some embodiments, the gene encodes a transcript with a sequence thathas at least 60%, at least 70%, at least 80%, at least 90%, at least95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455(see Table 4), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence thathas at least 60%, at least 70%, at least 80%, at least 90%, at least95%, or at least 99% sequence identity to any one of SEQ ID NOs1500-2177 (see Table 12), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence thathas at least 60%, at least 70%, at least 80%, at least 90%, at least95%, or at least 99% sequence identity to any one of SEQ ID NOs2204-2215, or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence thathas at least 60%, at least 70%, at least 80%, at least 90%, at least95%, or at least 99% sequence identity to any one of SEQ ID NOs2300-2893, or complements thereof.

In some embodiments, the one or more genetic variations comprise atleast 5, at least 10, at least 20, or at least 50 genetic variations.

In some embodiments, panel of polynucleic acids comprises at least 5, atleast 10, at least 20, or at least 50 polynucleic acids.

In some embodiments, the gene comprises a gene selected from the groupconsisting of gene numbers (GNs) 1-156 (in Table 3).

In some embodiments, the gene comprises a gene selected from the groupconsisting of gene numbers (GNs) in Table 6.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN491-GN492 in Table 29.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN493-GN762 in Table 31.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN763-GN765 in Table 48.

In some embodiments, the corresponding gene comprises a gene selectedfrom Tables 34-40, 42, 45A, 45B, 45C, 48, 50A, 50B and 51-62.

In some embodiments, the gene comprises a gene selected from the groupconsisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1,POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A,PIK3CD, PNP, MCEE, DOCK2 and ALG12 (see Table 13).

Provided herein is a method to predict an adverse responsiveness of asubject to a therapy, the method comprising detecting one or moregenetic variations that disrupt or modulate a gene of GN1-GN765 in apolynucleic acid sample from the subject; and using that detection as abiomarker for predicting a response of the subject to the therapy to beadverse, wherein the therapy is an immunosuppressive therapy.

Provided herein is a method of screening for a PML biomarker comprisingobtaining biological samples from subjects with PML; screening thebiological samples to obtain nucleic acid information; detecting one ormore genetic variations that disrupt or modulate a gene of GN1-GN765 ina polynucleic acid sample from a subject suspected of having PML; andusing that detection as a biomarker for predicting a response of thesubject to the therapy to be adverse, wherein the therapy is animmunosuppressive therapy.

Provided herein is a method of screening for a PML biomarker comprisingobtaining biological samples from subjects with PML; screening thebiological samples to obtain nucleic acid information; confirming eachbiological sample is not a duplicate of any other biological samplebased on the nucleic acid information; detecting one or more geneticvariations that disrupt or modulate a gene of GN1-GN765 in a polynucleicacid sample from a subject suspected of having PML; and using thatdetection as a biomarker for predicting a response of the subject to thetherapy to be adverse, wherein the therapy is an immunosuppressivetherapy.

Provided herein is a method of screening for a PML biomarker comprisingobtaining biological samples from subjects with PML; screening thebiological samples to obtain nucleic acid information; determining a sexgenotype for each biological sample based on the nucleic acidinformation; confirming the sex genotype of each sample is the same as asex phenotype of the subject from the subjects with PML; detecting oneor more genetic variations that disrupt or modulate a gene of GN1-GN765in a polynucleic acid sample from a subject suspected of having PML; andusing that detection as a biomarker for predicting a response of thesubject to the therapy to be adverse, wherein the therapy is animmunosuppressive therapy.

Provided herein is a method of treating a condition in a subject in needof natalizumab, interferon beta-1a, interferon beta-1b, glatirameracetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethylfumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab,diroximel fumarate or siponimod therapy, comprising: administering atherapeutically effective amount of natalizumab, interferon beta-1a,interferon beta-1b, glatiramer acetate, peginterferon beta-1a,teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone,rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod tothe subject, wherein the subject has a decreased risk of progressivemultifocal leukoencephalopathy (PML) due to an infection of the brain byJohn Cunningham virus (JCV), wherein the subject's decreased risk is dueto the absence of one or more genetic variations that disrupt ormodulate a corresponding gene according to Tables 3, 6, 29 and 31.

In some embodiments, the subject is identified as not having one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 29 and 31. In some embodiments, the subject isknown as not having one or more genetic variations that disrupt ormodulate a corresponding gene according to Tables 3, 6, 29 and 31. Insome embodiments, the subject is identified in a report (e.g., healthreport) as not having one or more genetic variations that disrupt ormodulate a corresponding gene according to Tables 3, 6, 29 and 31.

Also disclosed is a method of treating a condition in a subject in needof immunosuppressive medication therapy, comprising: administering atherapeutically effective amount of one or more immunosuppressivemedications to the subject, wherein the subject has a decreased risk ofprogressive multifocal leukoencephalopathy (PML) due to an infection ofthe brain by John Cunningham virus (JCV), wherein the subject'sdecreased risk is due to the absence of one or more genetic variationsthat disrupt or modulate a corresponding gene according to Tables 3, 6,29 and 31.

Also disclosed is a method of treating a condition in a subject in needof natalizumab therapy, comprising: administering a therapeuticallyeffective amount of natalizumab to the subject, wherein the subject hasa decreased risk of progressive multifocal leukoencephalopathy (PML) dueto an infection of the brain by John Cunningham virus (JCV), wherein thesubject's decreased risk is associated with an absence of one or moregenetic variations in the subject, wherein the subject has been testedfor a presence of the one or more genetic variations with a geneticassay and has been identified as not having the one or more geneticvariations, wherein the one or more genetic variations have an oddsratio (OR) of 3 or more, and wherein the OR is:[D_(D)/D_(N)]/[N_(D)/N_(N)], wherein: D_(D) is the number of subjects ina diseased cohort of subjects with the one or more genetic variations;D_(N) is the number of subjects in the diseased cohort without the oneor more genetic variations; N_(D) is the number of subjects in anon-diseased cohort of subjects with the one or more genetic variations;and N_(N) is the number of subjects in the non-diseased cohort withoutthe one or more genetic variations, wherein the diseased cohort ofsubjects have PML, and wherein the non-diseased cohort of subjects donot have PML.

In some embodiments, the one or more genetic variations have an OR of atleast 4, 5, 6, 7, 8, 9, or 10.

In some embodiments, the one or more genetic variations occur in one ormore immune function-related genes.

In some embodiments, the one or more immunosuppressive medicationscomprise a glucocorticoid, cytostatic, antibody, drug acting onimmunophilins, interferon, opioid, TNF binding protein, mycophenolate,small biological agent, small molecule, organic compound, or anycombination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic(AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4,anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent,anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb,anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctionalfusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 andanti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a inhibitor,CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor,FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factorreceptor-related gene [GITR] agonist, glutaminase inhibitor, Humanmonoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptortyrosine kinase inhibitor, neutrophil elastase inhibitor, NotchInhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L,ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator,Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combinationthereof.

In some embodiments, the one or more immunosuppressive medicationscomprise abatacept (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab,adrenocorticotropic hormone, agatolimod sodium, AJM300, aldesleukin,alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride,alvocidib, ambrisentan (e.g. LETAIRIS), aminocamptothecin, amiselimod,anakinra, andecaliximab, andrographolides (a botanical medicinal herbalso known as IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib,asparaginase, atacicept, atezolizumab, avelumab, azacitidine,azathioprine, bafetinib, baminercept, baricitinib, basiliximab,becatecarin, begelomab, belatacept, belimumab, bemcentinib,bendamustine, bendamustine (e.g. bendamustine hydrochloride), betalutinwith lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab,binimetinib, bleomycin, blinatumomab, BNZ-1, bortezomib (e.g. VELCADE),brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan,canakinumab, capecitabine, carboplatin, carfilzomib, carmustine,cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab(e.g. certolizumab pegol), cetuximab, chidamide, chlorambucil, CHS-131,cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab,clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine,cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine (e.g.AMPYRA), daprolizumab pegol, daratumumab, dasatinib, defactinib,defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate,dinaciclib, diroximel fumarate (e.g. VUMERITY), doxorubicin, doxorubicin(e.g. doxorubicin hydrochloride), durvalumab, duvelisib, duvortuxizumab,eculizumab (e.g. SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (aneuropeptide combination of metenkefalin and tridecactide), elezanumab,elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g. FUZEON),entinostat, entospletinib, enzastaurin, epacadostat, epirubicin,epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab,everolimus, evobrutinib, filgotinib, fingolimod (e.g. fingolimodhydrochloride), firategrast, fludarabine, fluorouracil, fontolizumab,forodesine hydrochloride, fostamatinib, galunisertib, ganetespib,ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib,glassia, glatiramer acetate, glembatumumab vedotin, glesatinib,golimumab (e.g. SIMPONI), guadecitabine, hydrocortisone,hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan,ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide,iguratimod, imatinib, imexon, IMU-838, infliximab, inotuzumabozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b,interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib,itacitinib, ixazomib, lapatinib, laquinimod, laromustine,ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole (e.g.FEMARA), levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib,lumiliximab, maraviroc (e.g. SELZENTRY), masitinib, mavrilimumab,melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone,milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab,mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox,muromonab-CD3, mycophenolate mofetil (e.g. mycophenolate mofetilhydrochloride), mycophenolic acid, namilumab, natalizumab, navitoclax,neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclaxmesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab,olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab,oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib,palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim (e.g.NEULASTA), peginterferon beta-1a, pegsunercept (peg stnf-ri),pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine,pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex,pixantrone, pleneva, plovamer acetate, polatuzumab vedotin,pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide,R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant il-12,relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir (e.g.NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246, sarilumab,secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod(e.g. MAYZENT), sirolimus (rapamycin), sirukumab, sitravatinib,sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenonepigallocatechin-gallate, tabalumab, tacrolimus (e.g. tacrolimusanhydrous), talabostat mesylate, talacotuzumab, tanespimycin,tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib,terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa,tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab,tofacitinib, TR-14035, tregalizumab, tremelimumab, treosulfan,ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab,varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax,vinblastine, vincristine, vinorelbine ditartrate, visilizumab,vismodegib, vistusertib, voriconazole (e.g. VFEND), vorinostat,vosaroxin, ziv-aflibercept, or any combination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise 2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoicacid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501,ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555,ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452,Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884,AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803,ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APLA12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797,ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASN002, ASP015K,ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188,ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991,AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312,BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100,BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492,BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, BIBR 796BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564,BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205,BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061,BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088,CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323,CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116,CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131,CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102,CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP,DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555,DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIA11, EOC202,ETBX-011, F8IL10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327,FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853,GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L,GS-1011, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249,GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781,GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769,GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286,HL2351, HL237, hLL1-DOX (IMMU-115), HLXO1, HM71224, HMPL-523, HSC835,HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125,INCAGNO2385, INCB018424, INCB028050, INCB039110, INCB047986,INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056,ISF35, ISIS 104838, ITF2357, JCARH125, JHL1011, JNJ 38518168,JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011,KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525,LAM-002A, LBECO101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399,LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367,LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013,MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538,MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280,MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812,MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibodyM-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022,MP-435, MP470, MRC375, MRG-106, MS-533, MSB111022, MSC2490484A, MT-1303,MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071,NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012,NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNC0215-0384,NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON0910Na,ONO-2506PO, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, PI446A-05,PBF-509, PBR06, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001,PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586,PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600,PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326,PRO131921, PR0283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001,RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077,RGB-03, RGI-2001, RHB-104, RNS60, R05045337, R07123520, Rob 803,RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323,SB683699, SBI-087, SC12267 (4SC-101), SCH 727965, SCIO-469, SD-101,SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136,SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996,SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023,SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901,TGR-1202, TH-302, TLO11, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015,TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R,VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844,XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365, or anycombination thereof.

In some embodiments, the one or more immunosuppressive medicationscomprise interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab, diroximel fumarate, siponimod or any combination thereof.In some embodiments, the one or more immunosuppressive medicationscomprises natalizumab.

In some embodiments, the one or more immunosuppressive medicationscomprise an antibody molecule or a fragment thereof. In someembodiments, the antibody molecule or a fragment thereof is arecombinant antibody molecule or a fragment thereof. In someembodiments, the antibody molecule or a fragment thereof is a humanizedantibody molecule or a fragment thereof. In some embodiments, theantibody molecule or fragment thereof is a humanized recombinantantibody molecule or fragment thereof. In some embodiments, the antibodymolecule or fragment thereof is a humanized recombinant IgG4K monoclonalantibody molecule or fragment thereof. In some embodiments, the antibodymolecule or fragment thereof comprises a sequence in CAS RegistryNumber: 189261-10-7. In some embodiments, the antibody molecule orfragment thereof comprises at least one antibody heavy chain. In someembodiments, the antibody molecule or fragment thereof comprises twoantibody heavy chains. In some embodiments, the antibody molecule orfragment thereof comprises at least one antibody light chain. In someembodiments, the antibody molecule or fragment thereof comprises twoantibody light chains. In some embodiments, the antibody molecule orfragment thereof comprises at least one antibody heavy chain and atleast one antibody light chain.

In some embodiments, the antibody molecule or fragment thereof isproduced in myeloma cells. In some embodiments, the antibody molecule orfragment thereof is produced in rabbit hybridoma cells.

In some embodiments, the antibody molecule or fragment thereof binds areceptor. In some embodiments, the antibody molecule or fragment thereofbinds an integrin. In some embodiments, the integrin is expressed onsurface of a leukocyte. In some embodiments, the leukocyte is aneutrophil. In some embodiments, the leukocyte is not a neutrophil. Insome embodiments, the antibody molecule or a fragment thereof binds α4β1integrin, α4β7 integrin, or both. In some embodiments, the antibodymolecule or a fragment thereof binds α4-subunit of α4β1 integrin, α4β7integrin, or both. In some embodiments, the antibody molecule or afragment thereof inhibits α4-mediated adhesion of a leukocyte to itsreceptor.

In some embodiments, the one or more immunosuppressive medicationscomprise an antibody or a fragment thereof, which comprises a sequencethat has at least about 50%, 60%, 70%, 80%, 90%, 95%, or 100% sequenceidentity to SEQ ID NO. 3275 (QVQLVQSGAE VKKPGASVKV SCKASGFNIK DTYIHWVRQAPGQRLEWMGR IDPANGYTKY DPKFQGRVTI TADTSASTAY MELSSLRSED TAVYYCAREGYYGNYGVYAM DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC LVKDYFPEPVTVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TKTYTCNVDH KPSNTKVDKRVESKYGPPCP SCPAPEFLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS QEDPEVQFNWYVDGVEVHNA KTKPREEQFN STYRVVSVLT VLHQDWLNGK EYKCKVSNKG LPSSIEKTISKAKGQPREPQ VYTLPPSQEE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPVLDSDGSFFLY SRLTVDKSRW QEGNVFSCSV MHEALHNHYT QKSLSLSLGK). In someembodiments, the antibody or fragment thereof comprises a sequence thathas about 50%-100% identity, for example, about 50%-60%, about 50%-70%,about 60%-70%, about 60%-80%, about 70%-80%, about 70%-90%, about80%-90%, about 80%-95%, about 90%-95%, about 90%-99%, about 90%-100%,about 95%-99%, or about 99%-100% sequence identity to SEQ ID NO. 3275.

In some embodiments, the one or more immunosuppressive medicationscomprise an antibody or a fragment thereof, which comprises a sequencethat has at least about 50%, 60%, 70%, 80%, 90%, 95%, or 100% sequenceidentity to SEQ ID NO. 3276 (DIQMTQSPSS LSASVGDRVT ITCKTSQDIN KYMAWYQQTPGKAPRLLIHY TSALQPGIPS RFSGSGSGRD YTFTISSLQP EDIATYYCLQ YDNLWTFGQGTKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQESVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL SSPVTKSFNRGEC). In someembodiments, the antibody or fragment thereof comprises a sequence thathas about 50%-100% identity, for example, about 50%-60%, about 50%-70%,about 60%-70%, about 60%-80%, about 70%-80%, about 70%-90%, about80%-90%, about 80%-95%, about 90%-95%, about 90%-99%, about 90%-100%,about 95%-99%, or about 99%-100% sequence identity to SEQ ID NO. 3276.

In some embodiments, the antibody molecule or fragment thereof comprisesat least one antibody heavy chain, or an α4-binding fragment thereof,comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and havingnon-human residues at framework positions 27-30 (Kabat numbering),wherein the positions 27-30 have the amino acid sequence Phe 27, Asn 28,Ile 29 and Lys 30.

In some embodiments, the antibody molecule or fragment thereof comprisesat least one antibody light chain, or an α4-binding fragment thereof,comprising: a light chain (LC) CDR1 with an amino acid sequence of SEQID NO.: 3277 (KTSQDINKYMA), a LC CDR2 with an amino acid sequence of SEQID NO.: 3278 (YTSALQP), and a LC CDR3 with an amino acid sequence of SEQID NO.: 3279 (LQYDNLWT).

In some embodiments, the antibody molecule or fragment thereof comprisesat least one antibody light chain, or an α4-binding fragment thereof,comprising: a light chain (LC) CDR1 with an amino acid sequence of SEQID NO.: 3280 (QASQDIIKYLN), a LC CDR2 with an amino acid sequence of SEQID NO.: 3281 (EASNLQA), and a LC CDR3 with an amino acid sequence of SEQID NO.: 3282 (QQYQSLPYT).

In some embodiments, the antibody molecule or fragment thereof comprisesat least one antibody light chain, or an α4-binding fragment thereof,comprising: a light chain (LC) CDR1 with an amino acid sequence of SEQID NO.: 3283 (KASQSVTNDVA), a LC CDR2 with an amino acid sequence of SEQID NO.: 3284 (YASNRYT), and a LC CDR3 with an amino acid sequence of SEQID NO.: 3285 (QQDYSSPYT).

In some embodiments, the antibody molecule or fragment thereof comprisesat least one antibody heavy chain, or an α4-binding fragment thereof,comprising: a heavy chain (HG) CDR1 with an amino acid sequence of SEQID NO.: 3286 (DTYIH), a HC CDR2 with an amino acid sequence of SEQ IDNO.: 3287 (RIDPANGYTKYDPKFQG), and a HC CDR3 with an amino acid sequenceof SEQ ID NO.: 3288 (EGYYGNYGVYAMDY).

In some embodiments, the antibody molecule or fragment thereof comprisesat least one antibody heavy chain, or an α4-binding fragment thereof,comprising: a heavy chain (HC) CDR1 with an amino acid sequence of SEQID NO.: 3289 (DTYMH), a HC CDR2 with an amino acid sequence of SEQ IDNO.: 3290 (RIDPASGDTKYDPKFQV), and a HC CDR3 with an amino acid sequenceof SEQ ID NO.: 3291 (DGMWVSTGYALDF).

In some embodiments, the antibody molecule or fragment thereof comprisesa humanized heavy chain, or an α4-binding fragment thereof, comprising:a variable heavy chain region selected from the group consisting of: SEQID NO.: 3292(MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTVSGFNIKDTYMHWVRQPPGRGLEWIGRIDPASGDTKYDPKFQVKATITADTSSNQFSLRLSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), SEQ ID NO.: 3293(QVQLQESGPGLVRPSQTLSLTCTVSGFNIKDTYMHWVRQPPGRGLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFSLRLSSVTSEDTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), SEQ IDNO.: 3294(MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTVSGFNIKDTYMHWVKQRPGRGLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFSLRLSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), SEQ ID NO.: 3295(MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTASGFNIKDTYMHWVRQPPGRGLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFSLRLSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), and SEQ ID NO.: 3296(QVQLVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQRLEWMGRIDPANGYTKYDPKFQGRVTITADTSASTAYMELSSLRSEDTAVYYCAREGYYGNYGVYAMDYWGQGTLVTVSS).

In some embodiments, the antibody molecule or fragment thereof comprisesa humanized light chain, or an α4-binding fragment thereof, comprising avariable light chain region selected from the group consisting of: SEQID NO.: 3297(MGWSCIILFLVATATGVHSDIQLTQSPSSLSASVGDRVTITCKASQSVTNDVAWYQQKPGKAPKLLIYYASNRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQDYSSPYTFGQGTKVEIKRK), SEQID NO.: 3298(MGWSCIILFLVATATGVHSSIVMTQSPSSLSASVGDRVTITCKASQSVTNDVAWYQQKPGKAPKLLIYYASNRYTGVPDRFSGSGYGTDFTFTISSLQPEDIATYYCQQDYSSPYTFGQGTKVEIKRK), SEQID NO.: 3299(MGWSCIILFLVATATGVHSDIQMTQSPSSLSASVGDRVTITCKASQSVTNDVAWYQQKPGKAPKLLIYYASNRYTGVPDRFSGSGYGTDFTFTISSLQPEDIATYYCQQDYSSPYTFGQGTKVEIKRK), andSEQ ID NO.: 3300(DIQMTQSPSSLSASVGDRVTITCKTSQDINKYMAWYQQTPGKAPRLLIHYTSALQPGIPSRFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLWTFGQGTKVEIKRTV).

In some embodiments, a biological product can be a regulatoryagency-approved biological product. For example, the biological productcan be approved by the U.S. Food and Drug Administration (FDA) and/orthe European medicines Agency (EMA). In some embodiments, the biologicalproduct can be a reference product. In some cases, the biologicalproduct can be a biosimilar product. In some embodiments, the biologicalproduct can be an interchangeable product.

In some embodiments, a biosimilar product can be similar to a referenceproduct (see, e.g. Table 67). In some embodiments, a biosimilar productcan have no clinically meaningful differences in terms of safety andeffectiveness from the reference product. In some embodiments, abiosimilar product can have the same clinically inactive components. Insome embodiments, a biosimilar product can have different clinicallyinactive components. In some embodiments, a biosimilar productspecifically interacts with a substrate and the reference productspecifically interacts with the same substrate. In some embodiments, aresponse rate of human subjects administered the biosimilar product canbe 50%-150% of the response rate of human subjects administered thereference product. For example, the response rate of human subjectsadministered the biosimilar product can be 50%-100%, 50%-110%, 50%-120%,50%-130%, 50%-140%, 50%-150%, 60%-100%, 60%-110%, 60%-120%, 60%-130%,60%-140%, 60%-150%, 70%-100%, 70%-110%, 70%-120%, 70%-130%, 70%-140%,70%-150%, 80%-100%, 80%-110%, 80%-120%, 80%-130%, 80%-140%, 80%-150%,90%-100%, 90%-110%, 90%-120%, 90%-130%, 90%-140%, 90%-150%, 100%-110%,100%-120%, 100%-130%, 100%-140%, 100%-150%, 110%-120%, 110%-130%,110%-140%, 110%-150%, 120%-130%, 120%-140%, 120%-150%, 130%-140%,130%-150%, or 140%-150% of the response rate of human subjectsadministered the reference product. In some embodiments, a biosimilarproduct and a reference product can utilize the same mechanism ormechanisms of action for the condition or conditions of use prescribed,recommended, or suggested in the proposed labeling, but only to extentthe mechanism or mechanisms are known for the reference product.

In some embodiments, an interchangeable product can be a biosimilarproduct that meets additional standards for interchangeability. In someembodiments, an interchangeable product can produce the same clinicalresult as a reference product in all of the reference product's licensedconditions of use. In some embodiments, an interchangeable product canbe substituted for the reference product by a pharmacist without theintervention of the health care provider who prescribed the referenceproduct. In some embodiments, when administered more than once to anindividual, the risk in terms of safety or diminished efficacy ofalternating or switching between use of the biological product and thereference product is not greater than the risk of using the referenceproduct without such alternation or switch. In some embodiments, aninterchangeable product can be a regulatory agency approved product. Insome embodiments, a response rate of human subjects administered theinterchangeable product can be 80%-120% of the response rate of humansubjects administered the reference product. For example, the responserate of human subjects administered the interchangeable product can be80%-100%, 80%-110%, 80%-120%, 90%-100%, 90%-110%, 90%-120%, 100%-110%,100%-120%, or 110%-120 of the response rate of human subjectsadministered the reference product.

In some embodiments, the condition is multiple sclerosis or Crohn'sdisease. In some embodiments, the condition is a relapsing form ofmultiple sclerosis.

In some embodiments, the natalizumab is administered via intravenousinfusion. In some embodiments, about 100 mg to about 500 mg of thenatalizumab is administered. In some embodiments, about 100 mg to about500 mg of the natalizumab is administered, for example, about 100 mg toabout 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg, about200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mg toabout 400 mg, about 300 mg to about 500 mg, or about 400 mg to about 500mg of the natalizumab is administered. In some embodiments, about 100 mgto about 500 mg of the natalizumab is administered via intravenousinfusion. In some embodiments, about 100 mg to about 500 mg of thenatalizumab is administered via intravenous infusion in four weeks. Insome embodiments, about 300 mg of the natalizumab is administered. Insome embodiments, about 300 mg of the natalizumab is administered viaintravenous infusion. In some embodiments, about 300 mg of thenatalizumab is administered via intravenous infusion in four weeks. Insome embodiments, at least about 10 mg of the natalizumab isadministered via intravenous infusion in six weeks. In some embodiments,at least about 10 mg of the natalizumab is administered via intravenousinfusion in eight weeks. In some embodiments, about 100 mg to about 500mg of the natalizumab is administered via intravenous infusion in sixweeks. In some embodiments, about 100 mg to about 500 mg of thenatalizumab is administered via intravenous infusion in eight weeks. Insome embodiments, about 300 mg of the natalizumab is administered viaintravenous infusion in six weeks. In some embodiments, about 300 mg ofthe natalizumab is administered via intravenous infusion in eight weeks

In some embodiments, the one or more immunosuppressive medicationscomprise dimethyl fumarate. In some embodiments, about 100 mg to about500 mg of the dimethyl fumarate is administered, for example, about 100mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg,about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mgto about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about500 mg of the dimethyl fumarate is administered. In some embodiments,about 120 mg of the dimethyl fumarate is administered. In someembodiments, about 240 mg of the dimethyl fumarate is administered.

In some embodiments, the one or more immunosuppressive medicationscomprise diroximel fumarate. In some embodiments, the one or moreimmunosuppressive medications comprise diroximel fumarate. In someembodiments, about 100 mg to about 500 mg of the diroximel fumarate isadministered, for example, about 100 mg to about 200 mg, about 100 mg toabout 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500mg, about 200 mg to about 300 mg, about 200 mg to about 400 mg, about200 mg to about 500 mg, about 300 mg to about 400 mg, about 300 mg toabout 500 mg, or about 400 mg to about 500 mg of the diroximel fumarateis administered. In some embodiments, about 400, 410, 420, 430, 440,450, 460, 462, 470, 480, 490 or 500 mg of the diroximel fumarate isadministered.

In some embodiments, the one or more immunosuppressive medicationscomprise fingolimod. In some embodiments, about 0.01 mg to about 5 mg ofthe fingolimod is administered, for example, about 0.01 mg to about 2mg, about 0.01 mg to about 3 mg, about 0.01 mg to about 4 mg, about 0.01mg to about 5 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 3mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 5 mg, about 0.2 mgto about 3 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 5 mg,about 0.3 mg to about 4 mg, about 0.3 mg to about 5 mg, about 0.4 mg toabout 5 mg, about 0.1 mg to about 0.2 mg, about 0.1 mg to about 0.3 mg,about 0.1 mg to about 0.4 mg, about 0.1 mg to about 0.5 mg, about 0.2 mgto about 0.3 mg, about 0.2 mg to about 0.4 mg, about 0.2 mg to about 0.5mg, about 0.3 mg to about 0.4 mg, about 0.3 mg to about 0.5 mg, about0.4 mg to about 0.5 mg, or about 0.4 mg to about 0.6 mg of thefingolimod is administered. In some embodiments, about 0.25 mg or 0.5 mgof the fingolimod is administered.

In some embodiments, the one or more immunosuppressive medicationscomprise rituximab. In some embodiments, about 100 mg to about 1000 mgof the rituximab is administered, for example, about 100 mg to about 200mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about100 mg to about 500 mg, about 100 mg to about 600 mg, about 100 mg toabout 700 mg, about 100 mg to about 800 mg, about 100 mg to about 900 mgof the rituximab is administered. The dose may be by weight or a fixeddose. In some embodiments, about 250 mg/m², 375 mg/m², 500 mg/m², 500mg, or 1000 mg of the rituximab is administered. In some embodiments,about 250 mg/m², 375 mg/m², 500 mg/m², 500 mg, or 1000 mg of therituximab is administered every week, every 2 weeks, every 4 weeks,every 8 weeks, or every 6 months. In some embodiments, about 250 mg/m²,375 mg/m², 500 mg/m², 500 mg, or 1000 mg of the rituximab isadministered every 8 weeks or every 6 months for treating MS. The totaldose can be from about 50 and 4000 mg, for example, from about 75 and3000 mg, from about 100 and 2000 mg, from about 100 and 1000 mg, fromabout 150 and 1000 mg, or from about 200 and 1000 mg, including doses ofabout 200, 300, 400, 500, 600, 700, 800, 900, 1000 mg, and 2000 mg.These doses may be given as a single dose or as multiple doses, forexample, two to four doses. Such doses may be done by infusions, forexample.

In some embodiments, the one or more immunosuppressive medicationscomprise siponimod. In some embodiments, about 0.1 mg to about 5 mg ofthe siponimod is administered. In some embodiments, about 1 mg or about2 mg of the siponimod is administered. In some embodiments, about 1 mgor about 2 mg of the siponimod is administered to a subject with aCYP2C9*1/*3 or CYP2C9*2/*3 genotype.

In some embodiments, the one or more genetic variations are associatedwith a risk of developing PML in a polynucleic acid sample from thesubject. In some embodiments, the one or more genetic variationscomprises a first genetic variation and a second genetic variation,wherein the first genetic variation disrupts or modulates acorresponding gene according to Tables 3 and 6, and wherein the secondgenetic variation disrupts or modulates a corresponding gene accordingto Tables 25A, 25B, and 26.

In some embodiments, the method comprises testing the subject for agenetic predisposition for PML with a genetic assay. In someembodiments, the genetic assay has a diagnostic yield of at least 5%. Insome cases, the genetic assay has a diagnostic yield of at least about5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some cases, thegenetic assay has a diagnostic yield of about 1%-5%, 1%-10%, 1%-20%,5%-10%, 5%-20%, 10%-20%, 10%-30%, 20%-30%, 20%-40%, 30%-40%, 30%-50%,40%-50%, 40%-60%, 50%-60%, 50%-70%, 60%-70%, 60%-80%, 70%-80%, 70%-90%,80%-90%, 80%-95%, 90%-95%, 90%-99%, 90%-100%, 95%-99%, or 99%-100%. Insome embodiments, the genetic assay has a diagnostic yield of at least20%.

In some embodiments, the one or more genetic variations disrupt ormodulate a corresponding gene according to Tables 13-18. In someembodiments, the one or more genetic variations disrupt or modulate acorresponding gene according to Tables 19-24. In some embodiments, theone or more genetic variations disrupt or modulate a corresponding geneaccording to Tables 28A, 28B, 29-41, 42, 45A, 45B, 45C, 48, 50A, 50B and51-62.

In some embodiments, the subject's decreased risk is further due to theabsence of one or more genetic variations that disrupt or modulate acorresponding gene according to Tables 25A, 25B, and 26.

In some embodiments, the one or more genetic variations disrupt ormodulate a corresponding gene selected from the group consisting of Homosapiens chromodomain helicase DNA binding protein 7 (CHD7), Homo sapiensinterferon induced with helicase C domain 1 (IFIH1), Homo sapiensimmunoglobulin lambda like polypeptide 1 (IGLL1), Homo sapiensmitochondrial antiviral signaling protein (MAVS), Homo sapiensphospholipase C gamma 2 (PLCG2), Homo sapiens SHANK-associated RH domaininteractor (SHARPIN), Homo sapiens T-cell immune regulator 1, ATPase H+transporting VO subunit a3 (TCIRG1), and any combination thereof. Insome embodiments, the one or more genetic variations comprisechr8:61654298 T>A, chr2:163136505 C>G, chr22:23917192 G>T, chr20:3846397C>T, chr16:81942175 A>G, chr8:145154222 G>A, chr11:67818269 G>A,chr8:145154824 A>C, chr22:23915745 G>A, chr20:3843027 C>A, or anycombination thereof.

In some embodiments, the one or more genetic variations disrupt ormodulate a corresponding gene selected from the group consisting ofFCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selectedfrom the group consisting of gene numbers (GNs) GN1-GN765. In someembodiments, the corresponding gene comprises a gene selected from thegroup consisting of gene numbers (GNs) GN1-GN241, GN243-GN369, andGN371-GN490.

In some embodiments, the one or more genetic variations are encoded by asequence with at least 60% sequence identity to SEQ ID NOs 1-172,2200-2203, or SRN1-SRN366, with 100% sequence identity to SEQ ID NOs1000-1329, 3000-3274, or with at least 80% and less than 100% sequenceidentity to GN1-GN765, or complements thereof. In some embodiments, theone or more genetic variations comprise a genetic variation encoded by aCNV with at least 60% sequence identity to SEQ ID NOs 1-172, 2200-2203,or complements thereof. In some embodiments, the one or more geneticvariations comprise a genetic variation encoded by a CNV sub-region(SRN) with at least 60% sequence identity to SRN1-SRN366, or complementsthereof. In some embodiments, the one or more genetic variationscomprise a genetic variation encoded by a single nucleotide variation(SNV) with a sequence of any one of SEQ ID NOs: 1000-1329, 3000-3274, orcomplements thereof. In some embodiments, the one or more geneticvariations are encoded by a sequence with at least 40% sequence identityto SEQ ID NOs 1-172, 2200-2203, or SRN1-SRN366, for example, at least40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,98%, 99%, or 100% sequence identity to SEQ ID NOs 1-172, 2200-2203, orSRN1-SRN366, or complements thereof. In some embodiments, the one ormore genetic variations are encoded by a sequence with at least 40%sequence identity to SEQ ID NOs 1000-1329, 3000-3274, for example, atleast 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%,97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs 1000-1329,3000-3274, or complements thereof. In some embodiments, the one or moregenetic variations are encoded by a sequence with at least 40% and lessthan 100% sequence identity to GN1-GN765, for example, at least 40% andless than 50%, at least 50% and less than 60%, at least 60% and lessthan 70%, at least 70% and less than 80%, at least 80% and less than90%, or at least 90% and less than 100% sequence identity to GN1-GN765,or complements thereof.

In some embodiments, the genetic assay comprises microarray analysis,PCR, sequencing, nucleic acid hybridization, or any combination thereof.

In some embodiments, the method comprises testing the subject with aJCV-antibody test, a CD62L test, or a CSF IgM oligoclonal bands test. Insome embodiments, the method comprises testing the subject with theJCV-antibody test, wherein the JCV-antibody test does not detect apresence of JCV. In some embodiments, the method comprises testing thesubject with the JCV-antibody test, wherein the JCV-antibody testdetects a presence of JCV. In some embodiments, the JCV-antibody testcomprises contacting a JCV detection reagent to a biological sample fromthe subject. In some embodiments, the JCV detection reagent is selectedfrom the group consisting of an anti-JCV antibody, a JCV specificprimer, and combinations thereof.

In some embodiments, the subject is identified as not having one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6,29, 31 and 48.

Provided herein is a kit, comprising reagents for assaying a polynucleicacid sample from a subject in need thereof for the presence of one ormore genetic variations that disrupt or modulate a gene of GN1-GN765. Insome embodiments, the one or more genetic variations disrupt or modulatea gene of GN1-GN241, GN243-GN369, and GN371-GN490.

Provided herein is a method of treating multiple sclerosis or Crohn'sdisease comprising: (a) testing a subject with multiple sclerosis orCrohn's disease for a genetic predisposition for PML with a geneticassay, wherein the genetic assay has a diagnostic yield of at least 20%,and (b) administering a therapeutically effective amount of natalizumab,interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab, diroximel fumarate or siponimod to the subject, wherein thetesting does not identify the subject as having the geneticpredisposition for PML.

In some embodiments, the method further comprises testing the subjectwith a JCV-antibody test. In some embodiments, the JCV-antibody testdoes not detect a presence of JCV. In some embodiments, the JCV-antibodytest detects a presence of JCV. In some embodiments, the genetic assaytests the subject for the presence of one or more genetic variationsthat disrupt or modulate a corresponding gene according to Tables 3, 6,25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of identifying a subject as not having arisk of developing PML, comprising: (a) analyzing a polynucleic acidsample from the subject for one or more genetic variations that disruptor modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26,29, 31 and 48; or Tables 3, 6, 29, 31 and 48, wherein a geneticvariation of the one or more genetic variations that disrupt or modulatea corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and48; or Tables 3, 6, 29, 31 and 48 is not present in the polynucleic acidsample; and (b) identifying the subject as not having a risk ofdeveloping PML.

Provided herein is a method of treating a condition in a subject in needof natalizumab, interferon beta-1a, interferon beta-1b, glatirameracetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethylfumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab or diroximel fumarate to the subject therapy, comprising:administering a therapeutically effective amount of natalizumab,interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab, diroximel fumarate or siponimod to the subject to thesubject, wherein the subject has a decreased risk of progressivemultifocal leukoencephalopathy (PML) due to an infection of the brain byJohn Cunningham virus (JCV), wherein the subject's decreased risk isassociated with an absence of one or more genetic variations in thesubject, wherein the subject has been tested for a presence of the oneor more genetic variations with a genetic assay and has been identifiedas not having the one or more genetic variations selected from Table 43.

Provided herein is a method of treating a condition in a subject in needof natalizumab, interferon beta-1a, interferon beta-1b, glatirameracetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethylfumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab or diroximel fumarate to the subject therapy, comprising:administering a therapeutically effective amount of natalizumab,interferon beta-1a, interferon beta-1b, glatiramer acetate,peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate,alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,ocrelizumab, diroximel fumarate or siponimod to the subject to thesubject, wherein the subject has a decreased risk of progressivemultifocal leukoencephalopathy (PML) due to an infection of the brain byJohn Cunningham virus (JCV), wherein the subject's decreased risk isassociated with a presence of one or more genetic variations in thesubject, wherein the subject has been tested for a presence of the oneor more genetic variations with a genetic assay and has been identifiedas having the one or more genetic variations selected from Table 44.

DETAILED DESCRIPTION OF THE DISCLOSURE

The details of one or more inventive embodiments are set forth in theaccompanying drawings, the claims, and in the description herein. Otherfeatures, objects, and advantages of inventive embodiments disclosed andcontemplated herein will be apparent from the description and drawings,and from the claims.

As used herein, unless otherwise indicated, the article “a” means one ormore unless explicitly otherwise provided for.

As used herein, unless otherwise indicated, terms such as “contain,”“containing,” “include,” “including,” and the like mean “comprising.”

As used herein, unless otherwise indicated, the term “or” can beconjunctive or disjunctive. As used herein, unless otherwise indicated,any embodiment can be combined with any other embodiment.

As used herein, unless otherwise indicated, some inventive embodimentsherein contemplate numerical ranges. When ranges are present, the rangesinclude the range endpoints. Additionally, every subrange and valuewithin the range is present as if explicitly written out.

As used herein, unless otherwise indicated, the term “about” in relationto a reference numerical value and its grammatical equivalents include arange of values plus or minus 10% from that value, such as a range ofvalues plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% fromthat value. For example, the amount “about 10” includes amounts from 9to 11.

As used herein, unless otherwise indicated, the term “biologicalproduct” refers to a virus, therapeutic serum, toxin, antitoxin,vaccine, blood, blood component or derivative, allergenic product,protein (any alpha amino acid polymer with a specific defined sequencethat is greater than 40 amino acids in size), or analogous product, orarsphenamine or derivative of arsphenamine (or any trivalent organicarsenic compound), applicable to the prevention, treatment, or cure of adisease or condition of human beings.

As used herein, unless otherwise indicated, the term “biosimilarproduct” refers to 1) a biological product having an amino acid sequencethat is identical to a reference product; 2) a biological product havinga different amino acid sequence (e.g., N- or C-terminal truncations)from a reference product; or 3) a biological product having a differentposttranslational modification (e.g., glycosylation or phosphorylation)from a reference product, wherein the biosimilar product and thereference product utilize the same mechanism or mechanisms of action forthe prevention, treatment, or cure of a disease or condition.

As used herein, “mechanism of action” refers to an interaction oractivity through which a drug product (e.g., a biological product)produces a pharmacological effect.

As used herein, unless otherwise indicated, the term “interchangeableproduct” refers to a biosimilar product, wherein a response rate of ahuman subject administered the interchangeable product is from 80% to120% of the response rate of the human subject administered thereference product.

As used herein, unless otherwise indicated, the term “reference product”refers to 1) a biological product having an amino acid sequence that isidentical to a biosimilar product; 2) a biological product having adifferent amino acid sequence (e.g., N- or C-terminal truncations) froma biosimilar product; or 3) a biological product having a differentposttranslational modification (e.g., glycosylation or phosphorylation)from a biosimilar product, wherein the reference product and thebiosimilar product utilize the same mechanism or mechanisms of actionfor the prevention, treatment, or cure of a disease or condition.

As used herein, unless otherwise indicated, any nonproprietary orgeneric name of a biological product includes the biological product andany biosimilar product thereof. For example, the nonproprietary name,filgrastim, refers to the biological product sold under the trade nameNEUPOGEN; it also includes the biosimilar product, filgrastim-sndz, soldunder the trade name ZARXIO. In another example, the nonproprietaryname, natalizumab, refers to the biological product sold under the tradename TYSABRI; it also includes any biosimilar product of the biologicalproduct.

All drug molecules and compounds provided herein include all salts,polymorphs, prodrugs, tautomers, zwitterionic forms, etc. thereof.

Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a rare and usuallyfatal viral disease characterized by progressive damage or inflammationof the white matter of the brain at multiple locations. The cause of PMLcan be a type of polyomavirus called the John Cunningham (JC) virus (orJCV), which can be harmless except in cases of weakened immune systems.While JCV is present at very high rates in the general population, PMLremains a rare disorder, albeit an important one because of the clinicalsequelae.

PML can occur in patients with severe immune deficiency, which allowsreactivation of the JC virus, such as: 1) most commonly among patientswith acquired immune deficiency syndrome (AIDS) that results frominfection with human immunodeficiency virus (HIV), 2) patients onimmunosuppressive medications like corticosteroids for organ transplant(e.g., renal, liver, lung, and heart) and in people with cancer (e.g.,Hodgkin's disease, leukemia, or lymphoma, and myeloproliferativeneoplasms such as myelofibrosis), and 3) individuals with autoimmunediseases (e.g., multiple sclerosis, rheumatoid arthritis, psoriasis, andsystemic lupus erythematosus) with therapies that depress the immuneresponse. Several immunosuppressive drugs have been reported in thecontext of drug-induced PML or drug-associated PML. For example, see:Melis et al. CNS Drugs. 2015; 29(10):879-91); Maas et al. J Neurol. 2016October; 263(10):2004-21; Colin et al. Fundam Clin Pharmacol. 2016 Oct.13. Immunosuppressive medications can include, but are not limited to, aglucocorticoid, cytostatic, antibody, drug acting on immunophilins,interferon, opioid, TNF binding protein, mycophenolate, small biologicalagent, small molecule, organic compound, A2aR antagonist, Akt inhibitor,anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic,anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb,anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1,bispecific anti-PD-1 and anti-LAG3 mAb, CDId ligand, CD40 agonist,Complement C5a inhibitor, CSFIR inhibitor, EZH2 inhibitor, FGFR3inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-inducedtumor necrosis factor receptor-related gene [GITR] agonist, glutaminaseinhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor,multitargeted receptor tyrosine kinase inhibitor, neutrophil elastaseinhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor,recombinant human Flt3L, ROCK inhibitor, selectivesphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4agonist, TLR9 agonist, abatacept (e.g. ORENCIA), abrilumab,acalabrutinib, adalimumab, adrenocorticotropic hormone, agatolimodsodium, AJM300, aldesleukin, alefacept, alemtuzumab, alisertib,alvespimycin hydrochloride, alvocidib, ambrisentan (e.g. LETAIRIS),aminocamptothecin, amiselimod, anakinra, andecaliximab, andrographolides(a botanical medicinal herb also known as IB-MS), anifrolumab,antithymocyte Ig, apatinib, apelisib, asparaginase, atacicept,atezolizumab, avelumab, azacitidine, azathioprine, bafetinib,baminercept, baricitinib, basiliximab, becatecarin, begelomab,belatacept, belimumab, bemeentinib, bendamustine, bendamustine (e.g.bendamustine hydrochloride), betalutin with lilotomab, bevacizumab,BIIB033, BIIB059, BIIB061, bimekizumab, binimetinib, bleomycin,blinatumomab, BNZ-1, bortezomib (e.g. VELCADE), brentuximab vedotin,bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab,capecitabine, carboplatin, carfilzomib, carmustine, cediranib maleate,cemiplimab, ceralifimod, cerdulatinib, certolizumab (e.g. certolizumabpegol), cetuximab, chidamide, chlorambucil, CHS-131, cilengitide,cirmtuzumab, cisplatin, cladribine, clazakizumab, clemastine,clioquinol, corticosteroids, cyclophosphamide, cyclosporine, cytarabine,cytotoxic chemotherapy, daclizumab, dalfampridine (e.g. AMPYRA),daprolizumab pegol, daratumumab, dasatinib, defactinib, defibrotide,denosumab, dexamethasone, diacerein, dimethyl fumarate, dinaciclib,diroximel fumarate (e.g. VUMERITY), doxorubicin, doxorubicin (e.g.doxorubicin hydrochloride), durvalumab, duvelisib, duvortuxizumab,eculizumab (e.g. SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (aneuropeptide combination of metenkefalin and tridecactide), elezanumab,elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g. FUZEON),entinostat, entospletinib, enzastaurin, epacadostat, epirubicin,epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab,everolimus, evobrutinib, filgotinib, fingolimod (e.g. fingolimodhydrochloride), firategrast, fludarabine, fluorouracil, fontolizumab,forodesine hydrochloride, fostamatinib, galunisertib, ganetespib,ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib,glassia, glatiramer acetate, glembatumumab vedotin, glesatinib,golimumab (e.g. SIMPONI), guadecitabine, hydrocortisone,hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan,ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide,iguratimod, imatinib, imexon, IMU-838, infliximab, inotuzumabozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b,interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib,itacitinib, ixazomib, lapatinib, laquinimod, laromustine,ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole (e.g.FEMARA), levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib,lumiliximab, maraviroc (e.g. SELZENTRY), masitinib, mavrilimumab,melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone,milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab,mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox,muromonab-CD3, mycophenolate mofetil (e.g. mycophenolate mofetilhydrochloride), mycophenolic acid, namilumab, natalizumab, navitoclax,neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclaxmesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab,olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab,oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib,palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim (e.g.NEULASTA), peginterferon beta-1a, pegsunercept (peg stnf-ri),pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine,pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex,pixantrone, pleneva, plovamer acetate, polatuzumab vedotin,pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide,R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant il-12,relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir (e.g.NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246, sarilumab,secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod(e.g. MAYZENT), sirolimus (rapamycin), sirukumab, sitravatinib,sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenonepigallocatechin-gallate, tabalumab, tacrolimus (e.g. tacrolimusanhydrous), talabostat mesylate, talacotuzumab, tanespimycin,tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib,terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa,tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab,tofacitinib, TR-14035, tregalizumab, tremelimumab, treosulfan,ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab,varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax,vinblastine, vincristine, vinorelbine ditartrate, visilizumab,vismodegib, vistusertib, voriconazole (e.g. VFEND), vorinostat,vosaroxin, ziv-aflibercept, 2B3-201, 3PRGD2, 4SC-202, 506U78,6,8-bis(benzylthio)octanoic acid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP,ABBV-257, ABL001, ABP 501, ABP 710, ABP 798, ABT-122, ABT-199, ABT-263,ABT-348, ABT-494, ABT-555, ABT-874, ABX-1431 HCl, ACP-196, ACP-319,ACT-128800, ACY-1215, AD 452, Ad-P53, ADCT-301, ADCT-402, ADL5859,ADS-5102, AFX-2, AGEN1884, AGEN2034, AGS67E, AIN457, AK106-001616,ALD518, ALKS 8700, ALT-803, ALT-803, ALX-0061, ALXN1007, ALXN6000,AMD3100, AMG 108, AMG 319, AMG 357, AMG 570, AMG 592, AMG 714, AMG 719,AMG 827, AMP-110, AP1903, APL A12, AP0866, APX005M, AQ4N, AR-42,ARN-6039, ARQ 531, ARRY-371797, ARRY-382, ARRY-438162, ART-I02, ART621,ASK8007, ASN002, ASP015K, ASP1707, ASP2408, ASP2409, ASP5094, AT-101,AT7519M, AT9283, ATA188, ATN-103, ATX-MS-1467, AVL-292, AVP-923,AZD4573, AZD5672, AZD5991, AZD6244, AZD6738, AZD9056, AZD9150, AZD9567,AZD9668, B-701, BAF312, BAY1830839, BBI608, BCD-054, BCD-055, BCD-063,BCD-089, BCD-100, BCD-132, BCD-145, BEZ235, BG000012, BG9924, BGB-3111,BGB-A333, BGG492, BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826,BI-1206, BIBR 796 BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS,BLZ945, BMMNC, BMN 673, BMS-247550, BMS-582949, BMS-817399, BMS-936558,BMS-936564, BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195,BMS-986205, BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001,BT061, BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137,CC-1088, CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519,CDP323, CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533,CGP 77116, CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR131, CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136,CNTO 148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086,CRx-102, CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543,DAC-HYP, DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505,DTRM-555, DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIAl1,EOC202, ETBX-011, F8IL10, FBTA05, FEDAA1106 (BAY85-8101), FGF401,FKB327, FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853,GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L,GS-1011, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249,GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781,GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769,GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286,HL2351, HL237, hLL1-DOX (IMMU-115), HLXO1, HM71224, HMPL-523, HSC835,HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125,INCAGNO2385, INCB018424, 1NCB028050, INCB039110, INCB047986,INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056,ISF35, ISIS 104838, ITF2357, JCARH125, JHL1011, JNJ 38518168,JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011,KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525,LAM-002A, LBEC0101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399,LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367,LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013,MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538,MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280,MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812,MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibodyM-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022,MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303,MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071,NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012,NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNC0215-0384,NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON0910Na,ONO-2506PO, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05,PBF-509, PBR06, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001,PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586,PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600,PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326,PRO131921, PR0283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001,RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077,RGB-03, RGI-2001, RHB-104, RNS60, R05045337, R07123520, Rob 803,RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323,SB683699, SBI-087, SC12267 (4SC-101), SCH 727965, SCIO-469, SD-101,SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136,SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996,SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023,SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901,TGR-1202, TH-302, TL011, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015,TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R,VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844,XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365 or anycombination thereof.

Exemplary small molecule immunosuppressive medications include dimethylfumarate, fingolimod, diroximel fumarate, and ruxolitinib. In someembodiments, an immunosuppressive therapy is classified as a Class 1(high risk) therapeutic agent, such as efalizumab and natalizumab asreported in Calabrese L. H. et al., Nat Rev Rheumatol. (2015).

In some cases, the immunosuppressive medications can be DNA and/or RNAcrosslinking agents, including alkylating agents, nitrogen mustardalkylating agents, topoisomerase inhibitors, anthracyclines, andplatinum-based anticancer drugs. In some cases, the immunosuppressivemedications can be kinase inhibitors, includingphosphoinositide-3-kinase, cyclin-dependent kinase (e.g., CDK9), Aurorakinase, ROCK, Akt, or PKC. In some cases, the immunosuppressivemedications can be tyrosine kinase inhibitors, including inhibitors ofthe fusion protein breakpoint cluster region-Abelson murine leukemiaviral oncogene homolog 1 (BCR-ABL), Bruton's tyrosine kinase (BTK),epidermal growth factor receptor (EGFR), Janus kinase (JAK), Syk, Lyn,MEK, FAK, BRAF, AXL, or vascular endothelial growth factor (VEGF). Insome cases, the immunosuppressive medications can be monoclonalantibodies and/or antibody-drug conjugates directed at proteinsincluding cluster of differentiation (CD) proteins, such as CD2, CD3,CD11a, CD20, CD30, CD52, CD-19, CD-38, CD-26, CD-37, CD-22, CD-33,CD-23, CD-74, CD-162, CD-79, CD-123, CD-4, CD-137, CD-27, CD-36, CD-39,CD-73, CD-226, CD-155, CD-40; interleukins (IL), such as IL-1, IL-2,IL-6, IL-12, IL-23; tumor necrosis factor (TNF) family proteins, such asTNFa; and integrins, such as integrin α4, α_(v)β₃, α_(v)β₅, α_(v)β₃, orα₂. In some cases, the immunosuppressive medications can be monoclonalantibodies and/or antibody-drug conjugates directed at Programmed celldeath receptor 1 (PD-1), Programmed cell death ligand 1 (PD-L1),Cytotoxic T-lymphocyte associated protein 4 (CTLA-4), Lymphocyteactivation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domaincontaining-3 (TIM-3), T-cell immunoreceptor with Ig and ITIM domains(TIGIT), also known as WUCAM or Vstm3, B and T lymphocyte attenuator(BTLA), Glucocorticoid-induced TNFR family related gene (GITR), OX40,HSP90, killer-cell immunoglobulin-like receptor (KIR), Toll-likereceptor 9 (TLR9), Toll-like receptor 4 (TLR4), Matrix metallopeptidase9 (MMP), Interferon receptor, Interferon gamma, Transforming growthfactor 1b (TGF1β), Insulin growth factor 1 receptor (IGF1 R), Fibroblastgrowth factor receptor (FGFrR3, FGFR4), Neuromedin B,Granulocyte-macrophage colony stimulating factor receptor (GM-CSF R),Natural killer cell receptor (NKG-2a), Leucine rich repeat andImmunoglobin-like domain-containing protein 1 (LINGO1), B-cellactivating factor (BAFF), Inducible T-cell co-stimulator (ICOS). In somecases, the monoclonal antibody/antibody-drug conjugate can activate thetarget.

In some cases, the monoclonal antibody/antibody-drug conjugate caninhibit the target. In some cases, the immunosuppressive medications canbe inhibitors of RANKL (receptor activator of nuclear factor kappa-Bligand). In some cases, the immunosuppressive medications can beinhibitors of histone deacetylase (HDAC). In some cases, theimmunosuppressive medications can be inhibitors of heat shock protein 90(HSP90). In some cases, the immunosuppressive medications can beinhibitors of cytidine deaminase (CDA). In some cases, theimmunosuppressive medications can be inhibitors of Hedgehog signalingpathway (including Sonic hedgehog and Smoothened). In some cases, theimmunosuppressive medications can be inhibitors of alpha-1-proteinase.In some cases, the immunosuppressive medications can be inhibitors ofcyclooxygenase 2 (COX2). In some cases, the immunosuppressivemedications can be inhibitors of complement (C5a). In some cases, theimmunosuppressive medications can be inhibitors of colony stimulatingfactor 1 receptor (CSF1R). In some cases, the immunosuppressivemedications can be inhibitors of Notch. In some cases, theimmunosuppressive medications can be inhibitors of kinesin. In somecases, the immunosuppressive medications can be inhibitors offarnesyltransferase. In some cases, the immunosuppressive medicationscan be inhibitors of poly(ADP-ribose) polymerase (PARP). In some cases,the immunosuppressive medications can be inhibitors of Neural PrecursorCell Expressed, Developmentally Down-Regulated (NEDD8). In some cases,the immunosuppressive medications can be inhibitors of dipeptidylpeptidase IV (DPP-IV). In some cases, the immunosuppressive medicationscan be inhibitors of leucine-rich repeat kinase 2 (LRRK2). In somecases, the immunosuppressive medications can be inhibitors of immunecheckpoint proteins. In some cases, the immunosuppressive medicationscan be inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1). In somecases, the immunosuppressive medications can be inhibitors of chemokinereceptors (CCR4, CCR5, CCR7). In some cases, the immunosuppressivemedications can be immunosuppression-inducing therapies such as T-cellsor regulatory T-cells modified with a chimeric antigen receptor (CAR-T,CAR-Tregs). In some cases, the immunosuppressive medications can bestructured lipids. In some cases, the immunosuppressive medications canbe Ras mimetic. In some cases, the immunosuppressive medications can beinhibitors of NOD-like receptor pyrin domain-containing protein 3(NLRP3). In some cases, the immunosuppressive medications can be mTORand/or calcineurin inhibitors. In some cases, the immunosuppressivemedications can be complement inhibitors. In some cases, theimmunosuppressive medications can be immunosuppressive antimetabolites,nucleoside metabolic inhibitors, imidazole nucleosides, nucleotideanalogs, nucleoside synthesis inhibitors, purine synthesis inhibitors,pyrimidine synthesis inhibitors, or pyrimidine synthase inhibitors. Insome cases, the immunosuppressive medications can be recombinantproteins, such as recombinant interferon beta, IL-2, IL-11, LymphotoxinB fusion protein, Therapeutic T cell receptor peptide vaccine,Keratinocyte growth factor, or Tumor necrosis factor (TNF) receptor.

In some cases, the immunosuppressive medications can besphingosine-1-phosphate receptor and/or nicotinic acetylcholine receptormodulators. For example, siponimod (BAF312) can be used for thetreatment of secondary progressive MS (Kappos L et al. 2018, PMID29576505). Another medication, ibudilast (MN-122), can be used for thetreatment of progressive MS (Fox R et al. 2016, PMID 27521810). In somecases, the immunosuppressive medications can be therapeutic antibodies,including Immunoglobulin G. In some cases, the immunosuppressivemedications can be asparaginase inhibitors. In some cases, theimmunosuppressive medications can be B-lymphocyte stimulator(BLyS)-specific inhibitor. In some cases, the immunosuppressivemedications can be T-cell costimulation modulators. In some cases, theimmunosuppressive medications can be cyclic polypeptideimmunosuppressants and/or synthetic polypeptides that modify immuneprocesses. In some cases, the immunosuppressive medications can becorticosteroids. In some cases, the immunosuppressive medications can becytotoxic chemotherapy drugs. In some cases, the immunosuppressivemedications can be cytotoxic glycopeptide antibiotics and/or mixturesthereof. In some cases, the immunosuppressive medications can bemolecules that inhibit pro-inflammatory cytokine production. In somecases, the immunosuppressive medications can be thalidomide analogues.

In some cases, the immunosuppressive medication can be a Complement C5ainhibitor. In some cases the immunosuppressive medication can be a CD40agonist. In some cases, the immunosuppressive medication can be a p38inhibitor. In some cases, the immunosuppressive medication can be aCSF1R inhibitor. In some cases, the immunosuppressive medication can bea MEK inhibitor. In some cases, the immunosuppressive medication can bea neutrophil elastase inhibitor. In some cases, the immunosuppressivemedication can be FGFrR3 inhibitor. In some cases, the immunosuppressivemedication can be anti-LAG3 mAb, Anti-CXCR, glucocorticoid-induced tumornecrosis factor receptor-related gene [GITR] agonist, IDO1 inhibitor,ICOS agonist, glutaminase inhibitor, recombinant human Flt3L, TLR9agonist, EZH2 inhibitor, anti-CTLA4 mAb, PD-1 inhibitor, PD-L1inhibitor, anti-PD-L1 mAb, FGFR4 inhibitor, bispecific anti-PD-1 andanti-LAG3 mAb, TLR4 agonist, Bcl-2 Inhibitor, or anti-LAG3 mAb. In somecases, the immunosuppressive medications can be inhibitors of celldegradation pathways, such as proteasome inhibitors. In some cases, theimmunosuppressive medication can be selected from A2aR antagonist, Aktinhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 proteintherapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb,anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb,anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor,Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1,bispecific anti-PD-1 and anti-LAG3 mAb, CDId ligand, CD40 agonist,Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-inducedtumor necrosis factor receptor-related gene [GITR] agonist, glutaminaseinhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor,multitargeted receptor tyrosine kinase inhibitor, neutrophil elastaseinhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor,recombinant human Flt3L, ROCK inhibitor, selectivesphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4agonist, TLR9 agonist.

In some cases, the immunosuppressive medication can be selected from2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoic acid,68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501, ABP710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555,ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452,Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884,AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803,ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APLA12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797,ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASN002, ASP015K,ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188,ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991,AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312,BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100,BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492,BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, BIBR 796BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564,BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205,BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061,BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088,CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323,CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116,CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131,CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102,CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP,DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555,DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIAl1, EOC202,ETBX-011, F8IL10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327,FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853,GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L,GS-1011, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249,GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781,GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769,GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286,HL2351, HL237, hLL1-DOX (IMMU-115), HLXO1, HM71224, HMPL-523, HSC835,HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125,INCAGNO2385, INCB018424, INCB028050, INCB039110, INCB047986,INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056,ISF35, ISIS 104838, ITF2357, JCARH125, JHL1101, JNJ 38518168,JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011,KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525,LAM-002A, LBECO101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399,LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367,LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013,MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538,MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280,MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812,MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibodyM-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022,MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303,MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071,NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012,NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNC0215-0384,NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON0910Na,ONO-2506PO, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05,PBF-509, PBR06, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001,PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586,PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600,PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326,PRO131921, PR0283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001,RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077,RGB-03, RGI-2001, RHB-104, RNS60, R05045337, R07123520, Rob 803,RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323,SB683699, SBI-087, SC12267 (4SC-101), SCH 727965, SCIO-469, SD-101,SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136,SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996,SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023,SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901,TGR-1202, TH-302, TLO11, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015,TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R,VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844,XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365.

PML can be diagnosed in a patient with a progressive course of thedisease, finding JC virus DNA in spinal fluid together with consistentwhite matter lesions on brain magnetic resonance imaging (MRI);alternatively, a brain biopsy can be diagnostic when the typicalhistopathology of demyelination, bizarre astrocytes, and enlargedoligodendroglial nuclei are present, coupled with techniques showing thepresence of JC virus. Characteristic evidence of PML on brain CT scanimages can be multifocal, non-contrast enhancing hypodense lesionswithout mass effect, but MRI can be more sensitive than CT. The mostcommon area of involvement can be the cortical white matter of frontaland parieto-occipital lobes, but lesions may occur anywhere in thebrain, like the basal ganglia, external capsule, and posterior cranialfossa structures like the brainstem and cerebellum.

In general, treatment of PML aims at reversing the immune deficiency toslow or stop the disease progress. Patients on an immunosuppressionregime can stop taking the immunosuppressive medication or plasmaexchange (PLEX) can be used to accelerate the removal of theimmunosuppressive medication that put the person at risk for PML.HIV-infected patients can start highly active antiretroviral therapy(HAART). Occurrence of PML can also occur in the context of immunereconstitution inflammatory syndrome (IRIS), wherein onset of PML canoccur or PML symptoms may get worse after cessation of immunosuppression(e.g., as reviewed by Pavlovic et al. Ther Adv Neurol Disord. 2015November; 8(6):255-73 and Bowen et al. Nat Rev Neurol. 2016 Oct. 27;12(11):662-674). For example, in MS patients that develop PML duringtreatment with natalizumab, IRIS often results when treatment is stoppedand PLEX is used to remove natalizumab from the patient's circulation.Treatment of IRIS in PML patients can include administration ofcorticosteroids. Other potential treatments of PML can includecidofovir, cytarabine, anti-malaria drug mefloquine, interleukin-2, and1-O-hexadecyloxypropyl-cidofovir (CMX001, aka brincidofovir). Asreviewed by Pavlovic (Ther Adv Neurol Disord. 2015 November;8(6):255-73), potential treatments for PML include antiviral agents(e.g., chlorpromazine, citalopram, mirtazapine, risperidone,ziprasidone, retro-2cycl, brefeldin A, cidofovir, brincidofovir,cytarabine, ganciclovir, leflunomide, topotecan, mefloquine,3-aminobenzamide, imatinib, and Ag122), immune response modulators(e.g., IFN-alpha, IL-2, IL-7, maraviroc, and glucocorticoids), andimmunization (e.g., recombinant human anti-JCV VP-1 monoclonalantibodies, JCV-specific cytotoxic T lymphocyte therapy, IL-7 plus JCVVP1 vaccine, and JCV oral vaccine).

The term “diagnostic yield” as used herein refers to the percentage ofcases that would identify the presence of one or more genetic variations(e.g., CNV, SNV) in a PML cohort using an assay. For example, if 40cases would identify the presence of one or more genetic variations(e.g., CNV, SNV) in a cohort of 100 PML patients, the diagnostic yieldof the assay is 40%. In some cases, the patients in the PML cohort areclinically diagnosed with PML. In some cases, a patient is clinicallydiagnosed with PML when JC virus DNA is present in spinal fluid andconsistent white matter lesions is present on brain magnetic resonanceimaging (MRI). In some cases, a patient is clinically diagnosed with PMLwhen typical histopathology of demyelination, bizarre astrocytes, andenlarged oligodendroglial nuclei are present in a brain biopsy, coupledwith the presence of JC virus. In some cases, the PML cohort has atleast 5 PML cases, for example, at least 5, 6, 7, 8, 9, 10, 20, 30, 40,50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000PML cases. In some cases, the PML cohort is a cohort listed herein. Forexample, the PML cohort is the PML patient cohort listed in Table 7. Insome cases, the assay is JCV-antibody assay. In some cases, the assay isnot JCV-antibody assay. In some cases, the assay is a genetic assay. Insome cases, the genetic assay tests the genetic predisposition for PML.

The genetic assay can comprise any method disclosed herein. In somecases, the genetic assay has a diagnostic yield of at least about 5%,6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some cases, the geneticassay has a diagnostic yield of about 1%-5%, 1%-10%, 1%-20%, 5%-10%,5%-20%, 10%-20%, 10%-30%, 20%-30%, 20%-40%, 30%-40%, 30%-50%, 40%-50%,40%-60%, 50%-60%, 50%-70%, 60%-70%, 60%-80%, 70%-80%, 70%-90%, 80%-90%,80%-95%, 90%-95%, 90%-99%, 90%-100%, 95%-99%, or 99%-100%.

Genetic Variations Associated with PML

Described herein, are methods that can be used to detect geneticvariations. Detecting specific genetic variations, for examplepolymorphic markers and/or haplotypes, copy number, absence or presenceof an allele, or genotype associated with a condition (e.g., disease ordisorder) as described herein, can be accomplished by methods known inthe art for analyzing nucleic acids and/or detecting sequences atpolymorphic or genetically variable sites, for example, amplificationtechniques, hybridization techniques, sequencing, microarrays/arrays, orany combination thereof. Thus, by use of these methods disclosed hereinor other methods available to the person skilled in the art, one or morealleles at polymorphic markers, including microsatellites, singlenucleotide polymorphisms (SNPs), single nucleotide variations (SNVs),insertions/deletions (indels), copy number variations (CNVs), or othertypes of genetic variations, can be identified in a sample obtained froma subject.

Genomic sequences within populations exhibit variability betweenindividuals at many locations in the genome. For example, the humangenome exhibits sequence variations that occur on average every 500 basepairs. Such genetic variations in polynucleic acid sequences arecommonly referred to as polymorphisms or polymorphic sites. As usedherein, a polymorphism, e.g., genetic variation, includes a variation inthe sequence of the genome amongst a population, such as allelicvariations and other variations that arise or are observed. Thus, apolymorphism refers to the occurrence of two or more geneticallydetermined alternative sequences or alleles in a population. Thesedifferences can occur in coding (e.g., exonic) and non-coding (e.g.,intronic or intergenic) portions of the genome, and can be manifested ordetected as differences in polynucleic acid sequences, gene expression,including, for example transcription, processing, translation,transport, protein processing, trafficking, DNA synthesis; expressedproteins, other gene products or products of biochemical pathways or inpost-translational modifications and any other differences manifestedamongst members of a population. Polymorphisms that arise as the resultof a single base change, such as single nucleotide polymorphisms (SNPs)or single nucleotide variations (SNVs), can include an insertion,deletion or change in one nucleotide. A polymorphic marker or site isthe locus at which divergence occurs. Such sites can be as small as onebase pair (an SNP or SNV). Polymorphic markers include, but are notlimited to, restriction fragment length polymorphisms (RFLPs), variablenumber of tandem repeats (VNTRs), hypervariable regions, minisatellites,dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats andother repeating patterns, simple sequence repeats and insertionalelements, such as Alu. Polymorphic forms also are manifested asdifferent mendelian alleles for a gene. Polymorphisms can be observed bydifferences in proteins, protein modifications, RNA expressionmodification, DNA and RNA methylation, regulatory factors that altergene expression and DNA replication, and any other manifestation ofalterations in genomic polynucleic acid or organelle polynucleic acids.Those skilled in the art can appreciate that polymorphisms are sometimesconsidered to be a subclass of variations, defined on the basis of aparticular frequency cutoff in a population. For example, in someembodiments, polymorphisms are considered to genetic variants/variationsthat occur at >1%, or >5%, frequency in the population.

In some embodiments, these genetic variations can be found to beassociated with one or more disorders and/or diseases using the methodsdisclosed herein. In some embodiments, these genetic variations can befound to be associated with absence of one or more disorders and/ordiseases (e.g. the one or more variants are protective againstdevelopment of the disorder and/or diseases) using the methods disclosedherein.

In some embodiments, these genetic variations comprise point mutations,polymorphisms, single nucleotide polymorphisms (SNPs), single nucleotidevariations (SNVs), translocations, insertions, deletions,amplifications, inversions, interstitial deletions, copy numbervariations (CNVs), structural variation (SV), loss of heterozygosity, orany combination thereof. As genetic variation includes any deletion,insertion or base substitution of the genomic DNA of one or moreindividuals in a first portion of a total population which therebyresults in a difference at the site of the deletion, insertion or basesubstitution relative to one or more individuals in a second portion ofthe total population. Thus, the term “genetic variation” encompasses“wild type” or the most frequently occurring variation, and alsoincludes “, mutant,” or the less frequently occurring variation. In someembodiments, a wild type allele may be referred to as an ancestralallele.

As used herein, a target molecule that is “associated with” or“correlates with” a particular genetic variation is a molecule that canbe functionally distinguished in its structure, activity, concentration,compartmentalization, degradation, secretion, and the like, as a resultof such genetic variation. In some embodiments polymorphisms (e.g.,polymorphic markers, genetic variations, or genetic variants) cancomprise any nucleotide position at which two or more sequences arepossible in a subject population. In some embodiments, each version of anucleotide sequence, with respect to the polymorphism/variation, canrepresent a specific allele of the polymorphism/variation. In someembodiments, genomic DNA from a subject can contain two alleles for anygiven polymorphic marker, representative of each copy of the marker oneach chromosome. In some embodiments, an allele can be a nucleotidesequence of a given location on a chromosome. Polymorphisms/variationscan comprise any number of specific alleles. In some embodiments of thedisclosure, a polymorphism/variation can be characterized by thepresence of two or more alleles in a population. In some embodiments,the polymorphism/variation can be characterized by the presence of threeor more alleles. In some embodiments, the polymorphism/variation can becharacterized by four or more alleles, five or more alleles, six or morealleles, seven or more alleles, nine or more alleles, or ten or morealleles. In some embodiments an allele can be associated with one ormore diseases or disorders, for example, a PML risk allele can be anallele that is associated with increased or decreased risk of developingPML. In some embodiments, genetic variations and alleles can be used toassociate an inherited phenotype with a responsible genotype. In someembodiments, a PML risk allele can be a variant allele that isstatistically associated with a screening of PML. In some embodiments,genetic variations can be of any measurable frequency in the population,for example, a frequency higher than 10%, a frequency from 5-10%, afrequency from 1-5%, a frequency from 0.1-1%, or a frequency below 0.1%.As used herein, variant alleles can be alleles that differ from areference allele. As used herein, a variant can be a segment of DNA thatdiffers from the reference DNA, such as a genetic variation. In someembodiments, genetic variations can be used to track the inheritance ofa gene that has not yet been identified, but whose approximate locationis known.

As used herein, a “haplotype” can be information regarding the presenceor absence of one or more genetic markers in a given chromosomal regionin a subject. In some embodiments, a haplotype can be a segment of DNAcharacterized by one or more alleles arranged along the segment, forexample, a haplotype can comprise one member of the pair of alleles foreach genetic variation or locus. In some embodiments, the haplotype cancomprise two or more alleles, three or more alleles, four or morealleles, five or more alleles, or any combination thereof, wherein, eachallele can comprise one or more genetic variations along the segment.

In some embodiments, a genetic variation can be a functional aberrationthat can alter gene function, gene expression, polypeptide expression,polypeptide function, or any combination thereof. In some embodiments, agenetic variation can be a loss-of-function mutation, gain-of-functionmutation, dominant negative mutation, or reversion. In some embodiments,a genetic variation can be part of a gene's coding region or regulatoryregion. Regulatory regions can control gene expression and thuspolypeptide expression. In some embodiments, a regulatory region can bea segment of DNA wherein regulatory polypeptides, for example,transcription or splicing factors, can bind. In some embodiments aregulatory region can be positioned near the gene being regulated, forexample, positions upstream or downstream of the gene being regulated.In some embodiments, a regulatory region (e.g., enhancer element) can beseveral thousands of base pairs upstream or downstream of a gene.

In some embodiments, variants can include changes that affect apolypeptide, such as a change in expression level, sequence, function,localization, binding partners, or any combination thereof. In someembodiments, a genetic variation can be a frameshift mutation, nonsensemutation, missense mutation, neutral mutation, or silent mutation. Forexample, sequence differences, when compared to a reference nucleotidesequence, can include the insertion or deletion of a single nucleotide,or of more than one nucleotide, resulting in a frame shift; the changeof at least one nucleotide, resulting in a change in the encoded aminoacid; the change of at least one nucleotide, resulting in the generationof a premature stop codon; the deletion of several nucleotides,resulting in a deletion of one or more amino acids encoded by thenucleotides; the insertion of one or several nucleotides, such as byunequal recombination or gene conversion, resulting in an interruptionof the coding sequence of a reading frame; duplication of all or a partof a sequence; transposition; or a rearrangement of a nucleotidesequence. Such sequence changes can alter the polypeptide encoded by thenucleic acid, for example, if the change in the nucleic acid sequencecauses a frame shift, the frame shift can result in a change in theencoded amino acids, and/or can result in the generation of a prematurestop codon, causing generation of a truncated polypeptide. In someembodiments, a genetic variation associated with PML can be a synonymouschange in one or more nucleotides, for example, a change that does notresult in a change in the amino acid sequence. Such a polymorphism can,for example, alter splice sites, affect the stability or transport ofmRNA, or otherwise affect the transcription or translation of an encodedpolypeptide. In some embodiments, a synonymous mutation can result inthe polypeptide product having an altered structure due to rare codonusage that impacts polypeptide folding during translation, which in somecases may alter its function and/or drug binding properties if it is adrug target. In some embodiments, the changes that can alter DNAincrease the possibility that structural changes, such as amplificationsor deletions, occur at the somatic level. A polypeptide encoded by thereference nucleotide sequence can be a reference polypeptide with aparticular reference amino acid sequence, and polypeptides encoded byvariant nucleotide sequences can be variant polypeptides with variantamino acid sequences.

The most common sequence variants comprise base variations at a singlebase position in the genome, and such sequence variants, orpolymorphisms, are commonly called single nucleotide polymorphisms(SNPs) or single nucleotide variants (SNVs). In some embodiments, a SNPrepresents a genetic variant present at greater than or equal to 1%occurrence in a population and in some embodiments a SNP or an SNV canrepresent a genetic variant present at any frequency level in apopulation. A SNP can be a nucleotide sequence variation occurring whena single nucleotide at a location in the genome differs between membersof a species or between paired chromosomes in a subject. SNPs caninclude variants of a single nucleotide, for example, at a givennucleotide position, some subjects can have a ‘G’, while others can havea ‘C’. SNPs can occur in a single mutational event, and therefore therecan be two possible alleles possible at each SNP site; the originalallele and the mutated allele. SNPs that are found to have two differentbases in a single nucleotide position are referred to as biallelic SNPs,those with three are referred to as triallelic, and those with all fourbases represented in the population are quadallelic. In someembodiments, SNPs can be considered neutral. In some embodiments SNPscan affect susceptibility to a condition (e.g., PML). SNP polymorphismscan have two alleles, for example, a subject can be homozygous for oneallele of the polymorphism wherein both chromosomal copies of theindividual have the same nucleotide at the SNP location, or a subjectcan be heterozygous wherein the two sister chromosomes of the subjectcontain different nucleotides. The SNP nomenclature as reported hereinis the official Reference SNP (rs) ID identification tag as assigned toeach unique SNP by the National Center for Biotechnological Information(NCBI).

Another genetic variation of the disclosure can be copy numbervariations (CNVs). As used herein, “CNVs” include alterations of the DNAof a genome that results in an abnormal number of copies of one or moresections of DNA. In some embodiments, a CNV comprises a CNV-subregion.As used herein, a “CNV-subregion” includes a continuous nucleotidesequence within a CNV. In some embodiments, the nucleotide sequence of aCNV-subregion can be shorter than the nucleotide sequence of the CNV,and in another embodiment the CNV-subregion can be equivalent to the CNV(e.g., such as for some CNVs). CNVs can be inherited or caused by denovo mutation and can be responsible for a substantial amount of humanphenotypic variability, behavioral traits, and disease susceptibility.In some embodiments, CNVs of the current disclosure can be associatedwith susceptibility to one or more conditions, for example, PML. In someembodiments, CNVs can include a single gene or include a contiguous setof genes. In some embodiments, CNVs can be caused by structuralrearrangements of the genome, for example, unbalanced translocations orinversions, insertions, deletions, amplifications, and interstitialdeletions. In some embodiments, these structural rearrangements occur onone or more chromosomes. Low copy repeats (LCRs), which areregion-specific repeat sequences (also known as segmental duplications),can be susceptible to these structural rearrangements, resulting inCNVs. Factors such as size, orientation, percentage similarity and thedistance between the copies can influence the susceptibility of LCRs togenomic rearrangement. In addition, rearrangements may be mediated bythe presence of high copy number repeats, such as long interspersedelements (LINEs) and short interspersed elements (SINEs), often vianon-homologous recombination. For example, chromosomal rearrangementscan arise from non-allelic homologous recombination during meiosis orvia a replication-based mechanism such as fork stalling and templateswitching (FoSTeS) (Zhang F. et al., Nat. Genet. (2009) ormicrohomology-mediated break-induced repair (MMBIR) (Hastings P. J. etal., PLoS Genetics (2009). In some embodiments, CNVs are referred to asstructural variants, which are a broader class of variant that alsoincludes copy number neutral alterations such as balanced inversions andbalanced translocations.

CNVs can account for genetic variation affecting a substantialproportion of the human genome, for example, known CNVs can cover over15% of the human genome sequence (Estivill and Armengol, PLoS Genetics(2007)). CNVs can affect gene expression, phenotypic variation andadaptation by disrupting or impairing gene dosage, and can causedisease, for example, microdeletion and microduplication disorders, andcan confer susceptibility to diseases and disorders. Updated informationabout the location, type, and size of known CNVs can be found in one ormore databases, for example, the Database of Genomic Variants (See,MacDonald J R et al., Nucleic Acids Res., 42, D986-92 (2014), whichcurrently contains data for over 500,000 CNVs (as of May, 2016).

Other types of sequence variants can be found in the human genome andcan be associated with a disease or disorder, including but not limitedto, microsatellites. Microsatellite markers are stable, polymorphic,easily analyzed, and can occur regularly throughout the genome, makingthem especially suitable for genetic analysis. A polymorphicmicrosatellite can comprise multiple small repeats of bases, forexample, CA repeats, at a particular site wherein the number of repeatlengths varies in a population. In some embodiments, microsatellites,for example, variable number of tandem repeats (VNTRs), can be shortsegments of DNA that have one or more repeated sequences, for example,about 2 to 5 nucleotides long, that can occur in non-coding DNA. In someembodiments, changes in microsatellites can occur during geneticrecombination of sexual reproduction, increasing or decreasing thenumber of repeats found at an allele, or changing allele length.

The genetic variations disclosed herein can be associated with a risk ofdeveloping PML in a subject. In some cases, the subject can have adecreased risk due to the absence of one or more genetic variations thatdisrupt or modulate a corresponding gene according to Tables 1 to 26.For example, the subject can have a decreased risk due to the absence ofone or more genetic variations that disrupt or modulate a correspondinggene according to Tables 3 and 6. In some cases, the subject can have anincreased risk due to the presence of one or more genetic variationsthat disrupt or modulate a corresponding gene according to Tables 1 to26. For example, the subject can have an increased risk due to thepresence of one or more genetic variations that disrupt or modulate acorresponding gene according to Tables 3 and 6. In some cases, one ormore genes listed in Tables 25A, 25B, and 26 can be removed from any oneof the Tables 1-24. In some cases, one or more genes listed in Tables25A, 25B, and 26 can be added to any one of the Tables 1-24.

TABLE 25A Exemplary 8-gene panel RefSeq Gene Gene Disease Number SymbolModel Gene Source Source Annotation (GN) BAG3 AR Public db PMID:19229298, 19282432, 22984599, 27042682 175 BTK XLR Public db PMID:18281276, 23765059, 25930993, 26029204 180 CD40LG XLR Public db PMID:17360404, 21455173, 23765059, 26008899, 206 26029204 DOCK8 AR Public dbPMID: 23765059, 23887241, 26029204, 26454313 242 MAGT1 XLR Public dbPMID: 23887241, 25504528, 27873163 326 RAG1 AD AR Public db PMID:23122631, 23765059, 23887241, 25976673, 370 26029204, 26454313,27484032, 27808398 STAT1 AD AR Public db PMID: 23887241, 25645939,26029204, 26513235, 436 26743090, 27821552, 27873163 WAS XLR Both PMID:12874226, 14647476, 19782549, 20008220, 483 24753205, 26029204, 26371186

TABLE 25B Exemplary 16-gene panel RefSeq Gene Gene Disease Number SymbolModel Gene Source Source Annotation (GN) ADA AR Both PMID: 23765059,24135998, 25930993, 26029204, 1 26454313 BAG3 AR Public db PMID:19229298, 19282432, 22984599, 27042682 175 BTK XLR Public db PMID:18281276, 23765059, 25930993, 26029204 180 CD40LG XLR Public db PMID:14647476, 17360404, 21455173, 23765059, 206 26008899, 26029204 DNMT3B ARPublic db PMID: 23486536, 23765059, 26029204, 26851945 240 DOCK8 ARPublic db PMID: 23765059, 23887241, 26029204, 26454313 242 ITK AR Publicdb PMID: 14647476, 23765059, 26029204, 26454313 308 LCK AR Public dbPMID: 14647476, 23765059, 26029204, 26454313 316 PNP AR Both PMID:26029204, 26454313 354 RAG1 AD AR Public db PMID: 23122631, 23765059,23887241, 25976673, 370 26029204, 26454313, 27484032, 27808398 STATI ADAR Public db PMID: 23887241, 25645939, 26029204, 26513235, 436 26743090,27821552, 27873163 STAT3 AD Public db PMID: 23765059, 23887241,25645939, 25930993, 438 26029204, 27658964, 27873163 STK3 unknown BothPMID: 26029204 135 TYK2 AR Public db PMID: 26029204, 26513235, 27821552144 WAS XLR Both PMID: 12874226, 19782549, 20008220, 24753205, 48326029204, 26371186 WIPF1 AR Public db PMID: 23765059, 26029204, 26453379485

TABLE 26 Exemplary 2-gene panel RefSeq Exon NCBI Gene Gene Gene Gene #Symbol overlap ID Description RefSeq Summary (GN) ADA intronic 100adenosine This gene encodes an enzyme that catalyzes the 1 deaminasehydrolysis of adenosine to inosine. Various mutations have beendescribed for this gene and have been linked to human diseases.Deficiency in this enzyme causes a form of severe combinedimmunodeficiency disease (SCID), in which there is dysfunction of both Band T lymphocytes with impaired cellular immunity and decreasedproduction of immunoglobulins, whereas elevated levels of this enzymehave been associated with congenital hemolytic anemia. [provided byRefSeq, July 2008]. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: BC040226.1, X02994.1 [ECO:0000332] RNAseq introns ::mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] STK3intronic 6788 serine/threonine- This gene encodes a serine/threonineprotein kinase 135 protein kinase 3 activated by proapoptotic moleculesindicating the isoform 1 encoded protein functions as a growthsuppressor. Cleavage of the protein product by caspase removes theinhibitory C-terminal portion. The N-terminal portion is transported tothe nucleus where it homodimerizes to form the active kinase whichpromotes the condensation of chromatin during apoptosis. Multipletranscript variants encoding different isoforms have been found for thisgene. [provided by RefSeq, January 2012]. Transcript Variant: Thisvariant (1) encodes isoform 1. Publication Note: This RefSeq recordincludes a subset of the publications that are available for this gene.Please see the Gene record to access additional publications. Transcriptexon combination :: U26424.1, BC010640.2 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025084, ERS025088 [ECO:0000348]

Subjects

A “subject”, as used herein, can be an individual of any age or sex fromwhom a sample containing polynucleotides is obtained for analysis by oneor more methods described herein so as to obtain polynucleic acidinformation; for example, a male or female adult, child, newborn, orfetus. In some embodiments, a subject can be any target of therapeuticadministration. In some embodiments, a subject can be a test subject ora reference subject.

As used herein, a “cohort” can represent an ethnic group, a patientgroup, a particular age group, a group not associated with a particularcondition (e.g., disease or disorder), a group associated with aparticular condition (e.g., disease or disorder), a group ofasymptomatic subjects, a group of symptomatic subjects, or a group orsubgroup of subjects associated with a particular response to atreatment regimen or enrolled in a clinical trial. In some embodiments,a patient can be a subject afflicted with a condition (e.g., disease ordisorder). In some embodiments, a patient can be a subject not afflictedwith a condition (e.g., disease or disorder) and is consideredapparently healthy, or a normal or control subject. In some embodiments,a subject can be a test subject, a patient or a candidate for atherapeutic, wherein genomic DNA from the subject, patient, or candidateis obtained for analysis by one or more methods of the presentdisclosure herein, so as to obtain genetic variation information of thesubject, patient or candidate.

In some embodiments, the polynucleic acid sample can be obtainedprenatally from a fetus or embryo or from the mother, for example, fromfetal or embryonic cells in the maternal circulation. In someembodiments, the polynucleic acid sample can be obtained with theassistance of a health care provider, for example, to draw blood. Insome embodiments, the polynucleic acid sample can be obtained withoutthe assistance of a health care provider, for example, where thepolynucleic acid sample is obtained non-invasively, such as a salivasample, or a sample comprising buccal cells that is obtained using abuccal swab or brush, or a mouthwash sample.

The present disclosure also provides methods for assessing geneticvariations in subjects who are members of a target population. Such atarget population is in some embodiments a population or group ofsubjects at risk of developing the condition (e.g., disease ordisorder), based on, for example, other genetic factors, biomarkers,biophysical parameters, diagnostic testing such as magnetic resonanceimaging (MRI), family history of the condition, previous screening ormedical history, or any combination thereof.

The genetic variations of the present disclosure found to be associatedwith a condition (e.g., disease or disorder) can show similarassociation in other human populations. Particular embodimentscomprising subject human populations are thus also contemplated andwithin the scope of the disclosure. Such embodiments relate to humansubjects that are from one or more human populations including, but notlimited to, Caucasian, Ashkenazi Jewish, Sephardi Jewish, European,American, Eurasian, Asian, Central/South Asian, East Asian, MiddleEastern, African, Hispanic, Caribbean, and Oceanic populations. Europeanpopulations include, but are not limited to, Swedish, Norwegian,Finnish, Russian, Danish, Icelandic, Irish, Celt, English, Scottish,Dutch, Belgian, French, German, Spanish, Portuguese, Italian, Polish,Bulgarian, Slavic, Serbian, Bosnian, Czech, Greek and Turkishpopulations. The ethnic contribution in subjects can also be determinedby genetic analysis, for example, genetic analysis of ancestry can becarried out using unlinked microsatellite markers or single nucleotidepolymorphisms (SNPs) such as those set out in Smith et al., (Smith M. W.et al., Am. J. Hum. Genet., 74:1001 (2004)).

Certain genetic variations can have different population frequencies indifferent populations, or are polymorphic in one population but not inanother. The methods available and as thought herein can be applied topractice the present disclosure in any given human population. This caninclude assessment of genetic variations of the present disclosure, soas to identify those markers that give strongest association within thespecific population. Thus, the at-risk variants of the presentdisclosure can reside on different haplotype background and in differentfrequencies in various human populations.

Conditions and Immunosuppressive Medications

In some embodiments, a subject can be diagnosed or undiagnosed with acondition (e.g., disease or disorder), can be asymptomatic orsymptomatic, can have increased or decreased susceptibility to acondition (e.g., disease or disorder), can be currently under orpreviously under or not under a treatment for a condition (e.g., diseaseor disorder), or any combination thereof. In some embodiments, thecondition can be AIDS, cancer, organ transplant, or an autoimmunedisease. In some embodiments, the condition is PML.

In some embodiments, a subject can be diagnosed or undiagnosed with PML,can be asymptomatic or symptomatic, can have increased or decreasedsusceptibility to PML, can be currently under or previously under or notunder a treatment for PML, or any combination thereof. In someembodiments, a subject can be diagnosed or undiagnosed with AIDS (e.g.,individuals infected with HIV), can be asymptomatic or symptomatic, canhave increased or decreased susceptibility to AIDS, can be currentlyunder or previously under or not under a treatment for AIDS, or anycombination thereof. In some embodiments, a subject can be diagnosed orundiagnosed with cancer (e.g., Hodgkin's disease, leukemia, lymphoma, ormyelofibrosis), can be asymptomatic or symptomatic, can have increasedor decreased susceptibility to cancer, can be currently under orpreviously under or not under a treatment for cancer, or any combinationthereof. In some embodiments, a subject can be currently diagnosed orpreviously diagnosed or undiagnosed with an autoimmune disease (e.g.,multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupuserythematosus), can be asymptomatic or symptomatic, can have increasedor decreased susceptibility to an autoimmune disease, can be currentlyunder or previously under or not under a treatment for an autoimmunedisease, or any combination thereof.

The term “cancer” is meant to include all types of cancerous growths oroncogenic processes, metastatic tissues or malignantly transformedcells, tissues, or organs, irrespective of histopathologic type or stageof invasiveness. A metastatic tumor can arise from a multitude ofprimary tumor types, including but not limited to those of breast, lung,liver, colon and ovarian origin. Examples of cancers include, but arenot limited to, a fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma,lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma,Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer,esophageal cancer, rectal cancer, pancreatic cancer, ovarian cancer,prostate cancer, uterine cancer, cancer of the head and neck, skincancer, brain cancer, squamous cell carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinoma,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicularcancer, small cell lung carcinoma, non-small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma,myelofibrosis, or Kaposi sarcoma.

The term “autoimmune disease” is meant to include all types ofpathological states arising from abnormal immune responses of the bodyto substances and tissues that are normally present in the body.Examples of autoimmune diseases include, but are not limited to, Addisondisease, Anti-NMDA receptor encephalitis, antisynthetase syndrome,Aplastic anemia, autoimmune anemias, Autoimmune hemolytic anemia,Autoimmune pancreatitis, Behcet's Disease, bullous skin disorders,Celiac disease-sprue (gluten-sensitive enteropathy), chronic fatiguesyndrome, Chronic inflammatory demyelinating polyneuropathy, chroniclymphocytic leukemia, Crohn's disease, Dermatomyositis, Devic's disease,Erythroblastopenia, Evans syndrome, Focal segmental glomerulosclerosis,Granulomatosis with polyangiitis, Graves disease, Graves'ophthalmopathy, Guillain-Barre syndrome, Hashimoto thyroiditis,idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgA-mediatedautoimmune diseases, IgG4-related disease, Inflammatory bowel disease,Juvenile idiopathic arthritis, Multiple sclerosis, Myasthenia gravis,myeloma, non-Hodgkin's lymphoma, Opsoclonus myoclonus syndrome (OMS),Pemphigoid, Pemphigus, pemphigus vulgaris, Pernicious anemia,polymyositis, Psoriasis, pure red cell aplasia, Reactive arthritis,Rheumatoid arthritis, Sarcoidosis, scleroderma, Sjögren syndrome,Systemic lupus erythematosus, Thrombocytopenic purpura, Thromboticthrombocytopenic purpura, Type I diabetes, Ulcerative colitis,Vasculitis (e.g., vasculitis associated with anti-neutrophil cytoplasmicantibody) and Vitiligo.

In some embodiments, a subject can be currently treated with animmunosuppressive medication. In some embodiments, a subject can bepreviously treated with an immunosuppressive medication. In someembodiments, a subject can be not yet treated with an immunosuppressivemedication. The immunosuppressive medication can include but not limitedto glucocorticoids, cytostatics, antibodies, drugs acting onimmunophilins, interferons, opioids, TNF binding proteins,mycophenolate, or other small biological agents. For example,glucocorticoids can include but not limited to cortisol(hydrocortisone), cortisone, prednisone, prednisolone,methylprednisolone, dexamethasone, betamethasone, triamcinolone,beclometasone, fludrocortisone acetate, deoxycorticosterone acetate(DOCA), or aldosterone. Cytostatics can include but not limited tonitrogen mustards (e.g., cyclophosphamide), nitrosoureas, platinumcompounds, folic acid analogues such as methotrexate, purine analoguessuch as azathioprine and mercaptopurine, pyrimidine analogues such asfluorouracil, protein synthesis inhibitors, cytotoxic antibiotics suchas dactinomycin, anthracyclines, mitomycin C, bleomycin, or mithramycin.Antibodies can include but not limited to polyclonal antibodies such asatgam and thymoglobuline, monoclonal antibodies such as CD25- andCD3-directed antibodies, muromonab-CD3, basiliximab (e.g., SIMULECT),and daclizumab (e.g., ZENAPAX). Drugs acting on immunophilins caninclude but not limited to ciclosporin, tacrolimus, sirolimus, oreverolimus. TNF binding proteins can include but not limited toinfliximab (e.g., REMICADE), etanercept (e.g., ENBREL), or adalimumab(e.g., HUMIRA). Other small biological agents can include but notlimited to fingolimod, myriocin, and rituximab (e.g., RITUXAN).

In some embodiments, the immunosuppressive medication can be drugs fortreating multiple sclerosis include but not limited to interferonbeta-1a (e.g., AVONEX, REBIF), interferon beta-1b (e.g., BETASERON,EXTAVIA), glatiramer acetate (e.g., COPAXONE, GLATOPA), peginterferonbeta-1a (e.g., PLEGRIDY), teriflunomide (e.g., AUBAGIO), fingolimod(e.g., GILENYA), dimethyl fumarate (e.g., TECFIDERA), alemtuzumab (e.g.,LEMTRADA), mitoxantrone (e.g., NOVANTRONE), natalizumab (e.g., TYSABRI),daclizumab (e.g., ZINBRYTA), or ocrelizumab (e.g., OCREVUS).

In some embodiments, the immunosuppressive medication can be adalimumab(e.g., HUMIRA), alemtuzumab (e.g., LEMTRADA), alemtuzumab (e.g.,CAMPATH), azathioprine (e.g., IMURAN), belimumab (e.g., BENLYSTA),bevacizumab (e.g., AVASTIN), bortezomib (e.g., VELCADE), eculizumab(e.g., SOLIRIS), leflunomide, brentuximab vedotin (e.g., ADCETRIS),cetuximab (e.g., ERBITUX), cyclophosphamid, dimethyl fumarate (e.g.,TECFIDERA), efalizumab (e.g., RAPTIVA), fingolimod (e.g., GILENYA),fludarabine (e.g., FLUDARA), fumaric acid, imatinib (e.g., GLEEVEC,GLIVEC), infliximab (e.g., REMICADE), methotrexate (e.g., TREXALL,RHEUMATREX), mycophenolate mofetil (e.g., CELLCEPT), natalizumab (e.g.,TYSABRI), daclizumab (e.g., ZINBRYTA), rituximab (e.g., RITUXAN),vedolizumab (e.g., ENTYVIO), ruxolitinib (e.g., JAKAFI, JAKAVI), orocrelizumab (e.g., Ocrevus). For example, rituximab can be used to treatMS patients (e.g., off-label), both relapsing-remitting (RRMS) andprogressive (PMS) forms; for instance, as reported by Memon A et al.2018 (PMID 29309416), Alcala C et al. 2018 (PMID 29785523), andBerntsson S et al. 2018 (PMID 29797711).

In some embodiments, a method of treating a condition in a subject inneed of natalizumab therapy, comprises administering a therapeuticallyeffective amount of natalizumab to the subject, wherein the subject isidentified as not having one or more genetic variations that disrupt ormodulate a corresponding gene according to Tables 3 and 6. In someembodiments, a method of reducing a risk of a subject developing PMLcomprises administering a therapeutically effective amount ofnatalizumab to the subject, wherein the subject is identified as nothaving one or more genetic variations that disrupt or modulate acorresponding gene according to Tables 3 and 6. In some embodiments, thecondition is multiple sclerosis. In some embodiments, the condition isCrohn's disease. In some embodiments, a method of treating multiplesclerosis comprises administering natalizumab to a subject with multiplesclerosis, wherein the subject is identified as not having one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3 and 6. In some embodiments, a method of treatingCrohn's disease comprises administering natalizumab to a subject withCrohn's disease, wherein the subject is identified as not having one ormore genetic variations that disrupt or modulate a corresponding geneaccording to Tables 3 and 6. In some embodiments, a method of treatingmultiple sclerosis comprises testing a subject with multiple sclerosisfor the presence of one or more genetic variations that disrupt ormodulate a corresponding gene according to Tables 3 and 6, determiningthat the subject does not have the one or more genetic variations thatdisrupt or modulate a corresponding gene according to Tables 3 and 6,and administering natalizumab to the subject that was determined not tohave the one or more genetic variations that disrupt or modulate acorresponding gene according to Tables 3 and 6. In some embodiments, amethod of treating Crohn's disease comprises testing a subject withCrohn's disease for the presence of one or more genetic variations thatdisrupt or modulate a corresponding gene according to Tables 3 and 6,determining that the subject does not have the one or more geneticvariations that disrupt or modulate a corresponding gene according toTables 3 and 6, and administering natalizumab to the subject that wasdetermined not to have the one or more genetic variations that disruptor modulate a corresponding gene according to Tables 3 and 6. In someembodiments, a method of reducing a risk of a subject developing PMLcomprises testing a subject for the presence of one or more geneticvariations that disrupt or modulate a corresponding gene according toTables 3 and 6, determining that the subject has at least one of the oneor more genetic variations that disrupt or modulate a corresponding geneaccording to Tables 3 and 6, and advising against administeringnatalizumab to the subject that was determined to have at least one ofthe one or more genetic variations that disrupt or modulate acorresponding gene according to Tables 3 and 6. In some embodiments, thesubject has multiple sclerosis. In some embodiments, the subject hasCrohn's disease. In some embodiments, a method of treating multiplesclerosis comprises testing a subject with multiple sclerosis for thepresence of one or more genetic variations that disrupt or modulate acorresponding gene according to Tables 3 and 6, determining that thesubject has at least one of the one or more genetic variations thatdisrupt or modulate a corresponding gene according to Tables 3 and 6,and advising against administering natalizumab to the subject that wasdetermined to have at least one of the one or more genetic variationsthat disrupt or modulate a corresponding gene according to Tables 3 and6. In some embodiments, a method of treating Crohn's disease comprisestesting a subject with Crohn's disease for the presence of one or moregenetic variations that disrupt or modulate a corresponding geneaccording to Tables 3 and 6, determining that the subject has at leastone of the one or more genetic variations that disrupt or modulate acorresponding gene according to Tables 3 and 6, and advising againstadministering natalizumab to the subject that was determined to have atleast one of the one or more genetic variations that disrupt or modulatea corresponding gene according to Tables 3 and 6. In some embodiments,the advising comprises advising that administering natalizumab iscontraindicated. In some embodiments, the advising comprises advisingthat administering natalizumab increases the risk of the subjectdeveloping PML. In some embodiments, the advising comprises advisingthat administering natalizumab is a factor that increases the risk ofthe subject developing PML.

Samples

Samples that are suitable for use in the methods described herein can bepolynucleic acid samples from a subject. A “polynucleic acid sample” asused herein can include RNA or DNA, or a combination thereof. In anotherembodiment, a “polypeptide sample” (e.g., peptides or proteins, orfragments therefrom) can be used to ascertain information that an aminoacid change has occurred, which is the result of a genetic variant.Polynucleic acids and polypeptides can be extracted from one or moresamples including but not limited to, blood, saliva, urine, mucosalscrapings of the lining of the mouth, expectorant, serum, tears, skin,tissue, or hair. A polynucleic acid sample can be assayed forpolynucleic acid information. “Polynucleic acid information,” as usedherein, includes a polynucleic acid sequence itself, thepresence/absence of genetic variation in the polynucleic acid sequence,a physical property which varies depending on the polynucleic acidsequence (e.g., Tm), and the amount of the polynucleic acid (e.g.,number of mRNA copies). A “polynucleic acid” means any one of DNA, RNA,DNA including artificial nucleotides, or RNA including artificialnucleotides. As used herein, a “purified polynucleic acid” includescDNAs, fragments of genomic polynucleic acids, polynucleic acidsproduced using the polymerase chain reaction (PCR), polynucleic acidsformed by restriction enzyme treatment of genomic polynucleic acids,recombinant polynucleic acids, and chemically synthesized polynucleicacid molecules. A “recombinant” polynucleic acid molecule includes apolynucleic acid molecule made by an artificial combination of twootherwise separated segments of sequence, e.g., by chemical synthesis orby the manipulation of isolated segments of polynucleic acids by geneticengineering techniques. As used herein, a “polypeptide” includesproteins, fragments of proteins, and peptides, whether isolated fromnatural sources, produced by recombinant techniques, or chemicallysynthesized. A polypeptide may have one or more modifications, such as apost-translational modification (e.g., glycosylation, phosphorylation,etc.) or any other modification (e.g., pegylation, etc.). Thepolypeptide may contain one or more non-naturally-occurring amino acids(e.g., such as an amino acid with a side chain modification).

In some embodiments, the polynucleic acid sample can comprise cells ortissue, for example, cell lines. Exemplary cell types from which nucleicacids can be obtained using the methods described herein include, butare not limited to, the following: a blood cell such as a B lymphocyte,T lymphocyte, leukocyte, erythrocyte, macrophage, or neutrophil; amuscle cell such as a skeletal cell, smooth muscle cell or cardiacmuscle cell; a germ cell, such as a sperm or egg; an epithelial cell; aconnective tissue cell, such as an adipocyte, chondrocyte; fibroblast orosteoblast; a neuron; an astrocyte; a stromal cell; an organ specificcell, such as a kidney cell, pancreatic cell, liver cell, or akeratinocyte; a stem cell; or any cell that develops therefrom. A cellfrom which nucleic acids can be obtained can be a blood cell or aparticular type of blood cell including, for example, a hematopoieticstem cell or a cell that arises from a hematopoietic stem cell such as ared blood cell, B lymphocyte, T lymphocyte, natural killer cell,neutrophil, basophil, eosinophil, monocyte, macrophage, or platelet.Generally, any type of stem cell can be used including, withoutlimitation, an embryonic stem cell, adult stem cell, or pluripotent stemcell.

In some embodiments, a polynucleic acid sample can be processed for RNAor DNA isolation, for example, RNA or DNA in a cell or tissue sample canbe separated from other components of the polynucleic acid sample. Cellscan be harvested from a polynucleic acid sample using standardtechniques, for example, by centrifuging a cell sample and resuspendingthe pelleted cells, for example, in a buffered solution, for example,phosphate-buffered saline (PBS). In some embodiments, after centrifugingthe cell suspension to obtain a cell pellet, the cells can be lysed toextract DNA. In some embodiments, the nucleic acid sample can beconcentrated and/or purified to isolate DNA. All nucleic acid samplesobtained from a subject, including those subjected to any sort offurther processing, are considered to be obtained from the subject. Insome embodiments, standard techniques and kits known in the art can beused to extract RNA or DNA from a nucleic acid sample, including, forexample, phenol extraction, a QIAAMP® Tissue Kit (Qiagen, Chatsworth,Calif.), a WIZARD® Genomic DNA purification kit (Promega), or a QiagenAutopure method using Puregene chemistry, which can enable purificationof highly stable DNA well-suited for archiving.

In some embodiments, determining the identity of an allele ordetermining copy number can, but need not, include obtaining apolynucleic acid sample comprising RNA and/or DNA from a subject, and/orassessing the identity, copy number, presence or absence of one or moregenetic variations and their chromosomal locations within the genomicDNA (e.g. subject's genome) derived from the polynucleic acid sample.

The individual or organization that performs the determination need notactually carry out the physical analysis of a nucleic acid sample from asubject. In some embodiments, the methods can include using informationobtained by analysis of the polynucleic acid sample by a third party. Insome embodiments, the methods can include steps that occur at more thanone site. For example, a polynucleic acid sample can be obtained from asubject at a first site, such as at a health care provider or at thesubject's home in the case of a self-testing kit. The polynucleic acidsample can be analyzed at the same or a second site, for example, at alaboratory or other testing facility.

Nucleic Acids

The nucleic acids and polypeptides described herein can be used inmethods and kits of the present disclosure. In some embodiments,aptamers that specifically bind the nucleic acids and polypeptidesdescribed herein can be used in methods and kits of the presentdisclosure. As used herein, a nucleic acid can comprise adeoxyribonucleotide (DNA) or ribonucleotide (RNA), whether singular orin polymers, naturally occurring or non-naturally occurring,double-stranded or single-stranded, coding, for example a translatedgene, or non-coding, for example a regulatory region, or any fragments,derivatives, mimetics or complements thereof. In some embodiments,nucleic acids can comprise oligonucleotides, nucleotides,polynucleotides, nucleic acid sequences, genomic sequences,complementary DNA (cDNA), antisense nucleic acids, DNA regions, probes,primers, genes, regulatory regions, introns, exons, open-reading frames,binding sites, target nucleic acids and allele-specific nucleic acids.

A “probe,” as used herein, includes a nucleic acid fragment forexamining a nucleic acid in a specimen using the hybridization reactionbased on the complementarity of nucleic acid.

A “hybrid” as used herein, includes a double strand formed between anyone of the abovementioned nucleic acid, within the same type, or acrossdifferent types, including DNA-DNA, DNA-RNA, RNA-RNA or the like.

“Isolated” nucleic acids, as used herein, are separated from nucleicacids that normally flank the gene or nucleotide sequence (as in genomicsequences) and/or has been completely or partially purified from othertranscribed sequences (e.g., as in an RNA library). For example,isolated nucleic acids of the disclosure can be substantially isolatedwith respect to the complex cellular milieu in which it naturallyoccurs, or culture medium when produced by recombinant techniques, orchemical precursors or other chemicals when chemically synthesized. Insome instances, the isolated material can form part of a composition,for example, a crude extract containing other substances, buffer systemor reagent mix. In some embodiments, the material can be purified toessential homogeneity using methods known in the art, for example, bypolyacrylamide gel electrophoresis (PAGE) or column chromatography(e.g., HPLC). With regard to genomic DNA (gDNA), the term “isolated”also can refer to nucleic acids that are separated from the chromosomewith which the genomic DNA is naturally associated. For example, theisolated nucleic acid molecule can contain less than about 250 kb, 200kb, 150 kb, 100 kb, 75 kb, 50 kb, 25 kb, 10 kb, 5 kb, 4 kb, 3 kb, 2 kb,1 kb, 0.5 kb or 0.1 kb of the nucleotides that flank the nucleic acidmolecule in the gDNA of the cell from which the nucleic acid molecule isderived.

Nucleic acids can be fused to other coding or regulatory sequences canbe considered isolated. For example, recombinant DNA contained in avector is included in the definition of “isolated” as used herein. Insome embodiments, isolated nucleic acids can include recombinant DNAmolecules in heterologous host cells or heterologous organisms, as wellas partially or substantially purified DNA molecules in solution.Isolated nucleic acids also encompass in vivo and in vitro RNAtranscripts of the DNA molecules of the present disclosure. An isolatednucleic acid molecule or nucleotide sequence can be synthesizedchemically or by recombinant means. Such isolated nucleotide sequencescan be useful, for example, in the manufacture of the encodedpolypeptide, as probes for isolating homologous sequences (e.g., fromother mammalian species), for gene mapping (e.g., by in situhybridization with chromosomes), or for detecting expression of thegene, in tissue (e.g., human tissue), such as by Northern blot analysisor other hybridization techniques disclosed herein. The disclosure alsopertains to nucleic acid sequences that hybridize under high stringencyhybridization conditions, such as for selective hybridization, to anucleotide sequence described herein Such nucleic acid sequences can bedetected and/or isolated by allele- or sequence-specific hybridization(e.g., under high stringency conditions). Stringency conditions andmethods for nucleic acid hybridizations are well known to the skilledperson (see, e.g., Current Protocols in Molecular Biology, Ausubel, F.et al., John Wiley & Sons, (1998), and Kraus, M. and Aaronson, S.,Methods Enzymol., 200:546-556 (1991), the entire teachings of which areincorporated by reference herein.

Calculations of “identity” or “percent identity” between two or morenucleotide or amino acid sequences can be determined by aligning thesequences for optimal comparison purposes (e.g., gaps can be introducedin the sequence of a first sequence). The nucleotides at correspondingpositions are then compared, and the percent identity between the twosequences is a function of the number of identical positions shared bythe sequences (e.g. % identity=# of identical positions/total # ofpositions×100). For example, a position in the first sequence isoccupied by the same nucleotide as the corresponding position in thesecond sequence, then the molecules are identical at that position. Thepercent identity between the two sequences is a function of the numberof identical positions shared by the sequences, taking into account thenumber of gaps, and the length of each gap, which need to be introducedfor optimal alignment of the two sequences.

In some embodiments, the length of a sequence aligned for comparisonpurposes is at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, or at least 95%, of the length ofthe reference sequence. The actual comparison of the two sequences canbe accomplished by well-known methods, for example, using a mathematicalalgorithm. A non-limiting example of such a mathematical algorithm isdescribed in Karlin, S. and Altschul, S., Proc. Natl. Acad. Sci. USA,90-5873-5877 (1993). Such an algorithm is incorporated into the NBLASTand XBLAST programs (version 2.0), as described in Altschul, S. et al.,Nucleic Acids Res., 25:3389-3402 (1997). When utilizing BLAST and GappedBLAST programs, any relevant parameters of the respective programs(e.g., NBLAST) can be used. For example, parameters for sequencecomparison can be set at score=100, word length=12, or can be varied(e.g., W=5 or W=20). Other examples include the algorithm of Myers andMiller, CABIOS (1989), ADVANCE, ADAM, BLAT, and FASTA. In someembodiments, the percent identity between two amino acid sequences canbe accomplished using, for example, the GAP program in the GCG softwarepackage (Accelrys, Cambridge, UK).

“Probes” or “primers” can be oligonucleotides that hybridize in abase-specific manner to a complementary strand of a nucleic acidmolecule. Probes can include primers, which can be a single-strandedoligonucleotide probe that can act as a point of initiation oftemplate-directed DNA synthesis using methods including but not limitedto, polymerase chain reaction (PCR) and ligase chain reaction (LCR) foramplification of a target sequence. Oligonucleotides, as describedherein, can include segments or fragments of nucleic acid sequences, ortheir complements. In some embodiments, DNA segments can be between 5and 10,000 contiguous bases, and can range from 5, 10, 12, 15, 20, or 25nucleotides to 10, 15, 20, 25, 30, 40, 50, 100, 200, 500, 1000 or 10,000nucleotides. In addition to DNA and RNA, probes and primers can includepolypeptide nucleic acids (PNA), as described in Nielsen, P. et al.,Science 254: 1497-1500 (1991). A probe or primer can comprise a regionof nucleotide sequence that hybridizes to at least about 15, typicallyabout 20-25, and in certain embodiments about 40, 50, 60 or 75,consecutive nucleotides of a nucleic acid molecule.

The present disclosure also provides isolated nucleic acids, forexample, probes or primers, that contain a fragment or portion that canselectively hybridize to a nucleic acid that comprises, or consists of,a nucleotide sequence, wherein the nucleotide sequence can comprise atleast one polymorphism or polymorphic allele contained in the geneticvariations described herein or the wild-type nucleotide that is locatedat the same position, or the complements thereof. In some embodiments,the probe or primer can be at least 70% identical, at least 80%identical, at least 85% identical, at least 90% identical, or at least95% identical, to the contiguous nucleotide sequence or to thecomplement of the contiguous nucleotide sequence.

In some embodiments, a nucleic acid probe can be an oligonucleotidecapable of hybridizing with a complementary region of a gene associatedwith a condition (e.g., PML) containing a genetic variation describedherein. The nucleic acid fragments of the disclosure can be used asprobes or primers in assays such as those described herein.

The nucleic acids of the disclosure, such as those described above, canbe identified and isolated using standard molecular biology techniqueswell known to the skilled person. In some embodiments, DNA can beamplified and/or can be labeled (e.g., radiolabeled, fluorescentlylabeled) and used as a probe for screening, for example, a cDNA libraryderived from an organism. cDNA can be derived from mRNA and can becontained in a suitable vector. For example, corresponding clones can beisolated, DNA obtained fallowing in vivo excision, and the cloned insertcan be sequenced in either or both orientations by art-recognizedmethods to identify the correct reading frame encoding a polypeptide ofthe appropriate molecular weight. Using these or similar methods, thepolypeptide and the DNA encoding the polypeptide can be isolated,sequenced and further characterized.

In some embodiments, nucleic acid can comprise one or morepolymorphisms, variations, or mutations, for example, single nucleotidepolymorphisms (SNPs), single nucleotide variations (SNVs), copy numbervariations (CNVs), for example, insertions, deletions, inversions, andtranslocations. In some embodiments, nucleic acids can comprise analogs,for example, phosphorothioates, phosphoramidates, methyl phosphonate,chiralmethyl phosphonates, 2-O-methyl ribonucleotides, or modifiednucleic acids, for example, modified backbone residues or linkages, ornucleic acids combined with carbohydrates, lipids, polypeptide or othermaterials, or peptide nucleic acids (PNAs), for example, chromatin,ribosomes, and transcriptosomes. In some embodiments nucleic acids cancomprise nucleic acids in various structures, for example, A DNA, B DNA,Z-form DNA, siRNA, tRNA, and ribozymes. In some embodiments, the nucleicacid may be naturally or non-naturally polymorphic, for example, havingone or more sequence differences, for example, additions, deletionsand/or substitutions, as compared to a reference sequence. In someembodiments, a reference sequence can be based on publicly availableinformation, for example, the U.C. Santa Cruz Human Genome BrowserGateway (genome.ucsc.edu/cgi-bin/hgGateway) or the NCBI website(www.ncbi.nlm.nih.gov). In some embodiments, a reference sequence can bedetermined by a practitioner of the present disclosure using methodswell known in the art, for example, by sequencing a reference nucleicacid.

In some embodiments, a probe can hybridize to an allele, SNP, SNV, orCNV as described herein. In some embodiments, the probe can bind toanother marker sequence associated with PML as described herein.

One of skill in the art would know how to design a probe so thatsequence specific hybridization can occur only if a particular allele ispresent in a genomic sequence from a test nucleic acid sample. Thedisclosure can also be reduced to practice using any convenientgenotyping method, including commercially available technologies andmethods for genotyping particular genetic variations

Control probes can also be used, for example, a probe that binds a lessvariable sequence, for example, a repetitive DNA associated with acentromere of a chromosome, can be used as a control. In someembodiments, probes can be obtained from commercial sources. In someembodiments, probes can be synthesized, for example, chemically or invitro, or made from chromosomal or genomic DNA through standardtechniques. In some embodiments sources of DNA that can be used includegenomic DNA, cloned DNA sequences, somatic cell hybrids that containone, or a part of one, human chromosome along with the normal chromosomecomplement of the host, and chromosomes purified by flow cytometry ormicrodissection. The region of interest can be isolated through cloning,or by site-specific amplification using PCR.

One or more nucleic acids for example, a probe or primer, can also belabeled, for example, by direct labeling, to comprise a detectablelabel. A detectable label can comprise any label capable of detection bya physical, chemical, or a biological process for example, a radioactivelabel, such as ³²P or ³H, a fluorescent label, such as FITC, achromophore label, an affinity-ligand label, an enzyme label, such asalkaline phosphatase, horseradish peroxidase, or I2 galactosidase, anenzyme cofactor label, a hapten conjugate label, such as digoxigenin ordinitrophenyl, a Raman signal generating label, a magnetic label, a spinlabel, an epitope label, such as the FLAG or HA epitope, a luminescentlabel, a heavy atom label, a nanoparticle label, an electrochemicallabel, a light scattering label, a spherical shell label, semiconductornanocrystal label, such as quantum dots (described in U.S. Pat. No.6,207,392), and probes labeled with any other signal generating labelknown to those of skill in the art, wherein a label can allow the probeto be visualized with or without a secondary detection molecule. Anucleotide can be directly incorporated into a probe with standardtechniques, for example, nick translation, random priming, and PCRlabeling. A “signal,” as used herein, include a signal suitablydetectable and measurable by appropriate means, including fluorescence,radioactivity, chemiluminescence, and the like.

Non-limiting examples of label moieties useful for detection include,without limitation, suitable enzymes such as horseradish peroxidase,alkaline phosphatase, beta-galactosidase, or acetylcholinesterase;members of a binding pair that are capable of forming complexes such asstreptavidin/biotin, avidin/biotin or an antigen/antibody complexincluding, for example, rabbit IgG and anti-rabbit IgG; fluorophoressuch as umbelliferone, fluorescein, fluorescein isothiocyanate,rhodamine, tetramethyl rhodamine, eosin, green fluorescent protein,erythrosin, coumarin, methyl coumarin, pyrene, malachite green,stilbene, lucifer yellow, Cascade Blue, Texas Red,dichlorotriazinylamine fluorescein, dansyl chloride, phycoerythrin,fluorescent lanthanide complexes such as those including Europium andTerbium, cyanine dye family members, such as Cy3 and Cy5, molecularbeacons and fluorescent derivatives thereof, as well as others known inthe art as described, for example, in Principles of FluorescenceSpectroscopy, Joseph R. Lakowicz (Editor), Plenum Pub Corp, 2nd edition(July 1999) and the 6th Edition of the Molecular Probes Handbook byRichard P. Hoagland; a luminescent material such as luminol; lightscattering or plasmon resonant materials such as gold or silverparticles or quantum dots; or radioactive material include ¹⁴C, ¹²³I,¹²⁴I, ¹²⁵I, Tc99m, ³²P, ³³P, ³⁵S or ³H.

Other labels can also be used in the methods of the present disclosure,for example, backbone labels. Backbone labels comprise nucleic acidstains that bind nucleic acids in a sequence independent manner.Non-limiting examples include intercalating dyes such as phenanthridinesand acridines (e.g., ethidium bromide, propidium iodide, hexidiumiodide, dihydroethidium, ethidium homodimer-1 and -2, ethidiummonoazide, and ACMA); some minor grove binders such as indoles andimidazoles (e.g., Hoechst 33258, Hoechst 33342, Hoechst 34580 and DAPI);and miscellaneous nucleic acid stains such as acridine orange (alsocapable of intercalating), 7-AAD, actinomycin D, LDS751, andhydroxystilbamidine. All of the aforementioned nucleic acid stains arecommercially available from suppliers such as Molecular Probes, Inc.Still other examples of nucleic acid stains include the following dyesfrom Molecular Probes: cyanine dyes such as SYTOX Blue, SYTOX Green,SYTOX Orange, POPO-1, POPO-3, YOYO-1, YOYO-3, TOTO-1, TOTO-3, JOJO-1,LOLO-1, BOBO-1, BOBO-3, PO-PRO-1, PO-PRO-3, BO-PRO-1, BO-PRO-3,TO-PRO-1, TO-PRO-3, TO-PRO-5, JO-PRO-1, LO-PRO-1, YO-PRO-1, YO-PRO-3,PicoGreen, OliGreen, RiboGreen, SYBR Gold, SYBR Green I, SYBR Green II,SYBR DX, SYTO-40, −41, −42, −43, −44, −45 (blue), SYTO-13, −16, −24,−21, −23, −12, −11, −20, −22, −15, −14, −25 (green), SYTO-81, −80, −82,−83, −84, −85 (orange), SYTO-64, −17, −59, −61, −62, −60, −63 (red).

In some embodiments, fluorophores of different colors can be chosen, forexample, 7-amino-4-methylcoumarin-3-acetic acid (AMCA),5-(and-6)-carboxy-X-rhodamine, lissamine rhodamine B,5-(and-6)-carboxyfluorescein, fluorescein-5-isothiocyanate (FITC),7-diethylaminocoumarin-3-carboxylic acid,tetramethylrhodamine-5-(and-6)-isothiocyanate,5-(and-6)-carboxytetramethylrhodamine, 7-hydroxycoumarin-3-carboxylicacid, 6-[fluorescein 5-(and-6)-carboxamido]hexanoic acid,N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a diaza-3-indacenepropionicacid, eosin-5-isothiocyanate, erythrosin-5-isothiocyanate, TRITC,rhodamine, tetramethylrhodamine, R-phycoerythrin, Cy-3, Cy-5, Cy-7,Texas Red, Phar-Red, allophycocyanin (APC), and CASCADE™ blueacetylazide, such that each probe in or not in a set can be distinctlyvisualized. In some embodiments, fluorescently labeled probes can beviewed with a fluorescence microscope and an appropriate filter for eachfluorophore, or by using dual or triple band-pass filter sets to observemultiple fluorophores. In some embodiments, techniques such as flowcytometry can be used to examine the hybridization pattern of theprobes.

In other embodiments, the probes can be indirectly labeled, for example,with biotin or digoxygenin, or labeled with radioactive isotopes such as³²P and/or ³H. As a non-limiting example, a probe indirectly labeledwith biotin can be detected by avidin conjugated to a detectable marker.For example, avidin can be conjugated to an enzymatic marker such asalkaline phosphatase or horseradish peroxidase. In some embodiments,enzymatic markers can be detected using colorimetric reactions using asubstrate and/or a catalyst for the enzyme. In some embodiments,catalysts for alkaline phosphatase can be used, for example,5-bromo-4-chloro-3-indolylphosphate and nitro blue tetrazolium. In someembodiments, a catalyst can be used for horseradish peroxidase, forexample, diaminobenzoate.

One or more genes disclosed herein can be in conditions or molecularpathways related to various aspects of immune function including, butnot limited to, Type I interferon response (e.g., PMID 26052098), B cellreceptor pathway (e.g., Wikipathways WP23; PMID 22566564), RANKL/RANKsignaling pathway (e.g., Wikipathways WP2018), TCR signaling pathway(e.g., Wikipathways WP69), NF-kB signaling (e.g., PMID 28362430),JAK-STAT pathway (e.g., PMID 28255960), post-translational modificationbiology such as ubiquitination via LUBAC (e.g., PMID 23104095, 24958845,25086647, 26085218, 26111062, 26525107, 26848516, 26877205, 27178468,27786304, 27892465), Aicardi-Goutieres syndrome (e.g., PMID 26052098),eosinophilia (e.g., PMID 27222657), congenital neutropenia (e.g., PMID24753205), T cell receptor defects (e.g., PMID 25452106, 25636200,26246585, 26379669, 26453379, 28400082), and autophagy defects (e.g.,19229298, 22984599, 23222957, 26917586, 26953272, 27588602). In someembodiments, one or more genes disclosed herein can be related to JCvirus biology (e.g., PMID 15327898, 19282432, 19903823, 22984599,25910481). In some embodiments, one or more genes disclosed herein canbe antiviral immune response genes.

TABLE 27 Exemplary pathways and biology for PML risk genes (96-genepanel) B T Type cell Deu- cell I Auto- Auto- B re- biqui- Eosinophilia-re- inter- inflam- phagy cell ceptor tinase associated JC P13K RANKL/ Tceptor TLR feron matory de- de- path- path- immuno- virus Osteo- signal-RANK cell path- signal- path- Genes disease fects fects way waydeficiency biology petrosis ing pathway defects way ing way AP3B1 xAPOL1 x ASH1L ATM x x x x ATR x x BLM CARD11 x x x x x CDKN1B CHD7 xCLCN7 x DCLRE1C DDX58 x DOCK8 x x x EGR1 EPG5 x ETF1 FPR2 GATA2 x GF11 xHIVEP1 HIVEP2 HTR2A x IDO2 IFIH1 x IFNGR2 IFNLRI IGLL1 x x IKBKB x x x xx x x x x IL17F IL1B x x x x x IL21R x IRAK4 x x x x x ITSN2 JUN x x xKAT6B KCTD7 LIG4 x LRBA x x x MALL MAPK3 x x x x MAVS x MCEE MKL1 xMYD88 x x x x NBN NFKB1 x x x x x x x x x x NOD2 x x x x x NRIP1 PIAS1 xPIAS2 x PIK3CD x x PIK3CD- x AS1 PIK3R1 x x x x x x PKHD1 PLCG2 x x x xx x x PNPT1 POLA1 x POLE x PRF1 PRKCB x PRKCD x x x PRKCH PRKDC xPSTPIP1 x PTEN x PTPRC x x x RABGEF1 RAD51 x RAG1 x x x RAG2 x x x RIPK1x x x x RIPK3 x x RNF168 RTEL1 SHARPIN x x x x x x SKIV2L x SMAD4 xSTIM1 x x STIM2 STXBP2 TAP2 TBK1 x x TCIRG1 x TICAM1 x x x TLR3 x x x xTLR4 x x x x TNFRSF11A x x x x x x TNFRSF13B x x TNFRSF8 TP53 TRAF3 x xx x TRAFD1 x x x TRPM2 VPS45 WEE1 x ZAP70 x x x x

Table 27 contains a set of exemplary pathways and biology for PML riskgenes based on the 96-gene panel listed in Table 19. The genes disclosedherein, such as the genes in the 96-gene panel, can be grouped based onthe pathway or biological processes they are involved in.

Methods of Screening

As used herein, screening a subject comprises diagnosing or determining,theranosing, or determining the susceptibility to developing(prognosing) a condition, for example, PML. In particular embodiments,the disclosure is a method of determining a presence of, or asusceptibility to, PML, by detecting at least one genetic variation in asample from a subject as described herein. In some embodiments,detection of particular alleles, markers, variations, or haplotypes isindicative of a presence or susceptibility to a condition (e.g., PML).

While means for screening PML using a JCV antibody test exist, PML riskis not adequately assessed by the JCV antibody test alone. Thus thereexists a need for an improved screening test for assessing the risk ofdeveloping PML. Described herein are methods of screening an individualfor a risk of developing PML, including but not limited to, determiningthe identity and location of genetic variations, such as variations innucleotide sequence and copy number, and the presence or absence ofalleles or genotypes in one or more samples from one or more subjectsusing any of the methods described herein. In some embodiments,determining an association to having or developing PML can be performedby detecting particular variations that appear more frequently in testsubjects compared to reference subjects and analyzing the molecular andphysiological pathways these variations can affect.

Within any given population, there can be an absolute susceptibility ofdeveloping a disease or trait, defined as the chance of a persondeveloping the specific disease or trait over a specified time-period.Susceptibility (e.g., being at-risk) is typically measured by looking atvery large numbers of people, rather than at a particular individual. Asdescribed herein, certain copy number variations (genetic variations)and/or single nucleotide variations are found to be useful forsusceptibility assessment of PML. Susceptibility assessment can involvedetecting particular genetic variations in the genome of individualsundergoing assessment. Particular genetic variations are found morefrequently in individuals with PML, than in individuals without PML.Therefore, these genetic variations have predictive value for detectingPML, or a susceptibility to PML, in an individual. Without intending tobe limited by theory, it is believed that the genetic variationsdescribed herein to be associated with susceptibility of PML representfunctional variants predisposing to the disease. In some embodiments, agenetic variation can confer a susceptibility of the condition, forexample carriers of the genetic variation are at a different risk of thecondition than non-carriers. In some embodiments, the presence of agenetic variation is indicative of increased susceptibility to PML.

In some embodiments, screening can be performed using any of the methodsdisclosed, alone or in combination. In some embodiments, screening canbe performed using Polymerase Chain Reaction (PCR). In some embodimentsscreening can be performed using Array Comparative Genomic Hybridization(aCGH) to detect CNVs. In another preferred embodiment screening can beperformed using exome sequencing to detect SNVs, indels, and in somecases CNVs using appropriate analysis algorithms. In another preferredembodiment screening is performed using high-throughput (also known asnext generation) whole genome sequencing methods and appropriatealgorithms to detect all or nearly all genetic variations present in agenomic DNA sample. In some embodiments, the genetic variationinformation as it relates to the current disclosure can be used inconjunction with any of the above mentioned symptomatic screening teststo screen a subject for PML, for example, using a combination of aCGHand/or sequencing with a JCV screening test, such as the JCV antibodytest, CD62L test, or CSF IgM oligoclonal band test. In some embodiments,the L-selectin (CD62L) expressed by CD3⁺CD4⁺ T cells in, for example,cryopreserved peripheral blood mononuclear cells (PBMCs), can be abiomarker for JCV screening. A CD62L expression can be correlated withthe risk of PML.

In some embodiments, information from any of the above screening methods(e.g., specific symptoms, scoring matrix, or genetic variation data) canbe used to define a subject as a test subject or reference subject. Insome embodiments, information from any of the above screening methodscan be used to associate a subject with a test or reference population,for example, a subject in a population.

In one embodiment, an association with PML can be determined by thestatistical likelihood of the presence of a genetic variation in asubject with PML, for example, an unrelated individual or a first orsecond-degree relation of the subject. In some embodiments, anassociation with PML can be decided by determining the statisticallikelihood of the absence of a genetic variation in an unaffectedreference subject, for example, an unrelated individual or a first orsecond-degree relation of the subject. The methods described herein caninclude obtaining and analyzing a nucleic acid sample from one or moresuitable reference subjects.

In the present context, the term screening comprises diagnosis,prognosis, and theranosis. Screening can refer to any availablescreening method, including those mentioned herein. As used herein,susceptibility can be proneness of a subject towards the development ofPML, or towards being less able to resist PML than one or more controlsubjects. In some embodiments, susceptibility can encompass increasedsusceptibility. For example, particular nucleic acid variations of thedisclosure as described herein can be characteristic of increasedsusceptibility to PML. In some embodiments, particular nucleic acidvariations can confer decreased susceptibility, for example particularnucleic variations of the disclosure as described herein can becharacteristic of decreased susceptibility to development of PML.

As described herein, a genetic variation predictive of susceptibility toor presence of PML can be one where the particular genetic variation ismore frequently present in a group of subjects with the condition(affected), compared to the frequency of its presence in a referencegroup (control), such that the presence of the genetic variation isindicative of susceptibility to or presence of PML. In some embodiments,the reference group can be a population nucleic acid sample, forexample, a random nucleic acid sample from the general population or amixture of two or more nucleic acid samples from a population. In someembodiments, disease-free controls can be characterized by the absenceof one or more specific disease-associated symptoms, for example,individuals who have not experienced symptoms associated with PML. Insome embodiments, the disease-free control group is characterized by theabsence of one or more disease-specific risk factors, for example, atleast one genetic and/or environmental risk factor. In some embodiments,a reference sequence can be referred to for a particular site of geneticvariation. In some embodiments, a reference allele can be a wild-typeallele and can be chosen as either the first sequenced allele or as theallele from a control individual. In some embodiments, one or morereference subjects can be characteristically matched with one or moreaffected subjects, for example, with matched aged, gender or ethnicity.

A person skilled in the art can appreciate that for genetic variationswith two or more alleles present in the population being studied, andwherein one allele can be found in increased frequency in a group ofindividuals with PML in the population, compared with controls, theother allele of the marker can be found in decreased frequency in thegroup of individuals with the trait or disease, compared with controls.In such a case, one allele of the marker, for example, the allele foundin increased frequency in individuals with PML, can be the at-riskallele, while the other allele(s) can be a neutral or protective allele.

A genetic variant associated with PML can be used to predict thesusceptibility of the disease for a given genotype. For any geneticvariation, there can be one or more possible genotypes, for example,homozygote for the at-risk variant (e.g., in autosomal recessivedisorders), heterozygote, and non-carrier of the at-risk variant.Autosomal recessive disorders can also result from two distinct geneticvariants impacting the same gene such that the individual is a compoundheterozygote (e.g., the maternal allele contains a different mutationthan the paternal allele). Compound heterozygosity may result from twodifferent SNVs, two different CNVs, an SNV and a CNV, or any combinationof two different genetic variants but each present on a different allelefor the gene. For X-linked genes, males who possess one copy of avariant-containing gene may be affected, while carrier females, who alsopossess a wild-type gene, may remain unaffected. In some embodiments,susceptibility associated with variants at multiple loci can be used toestimate overall susceptibility. For multiple genetic variants, therecan be k (k=3{circumflex over ( )}n*2P) possible genotypes; wherein ncan be the number of autosomal loci and p can be the number of gonosomal(sex chromosomal) loci. Overall susceptibility assessment calculationscan assume that the relative susceptibilities of different geneticvariants multiply, for example, the overall susceptibility associatedwith a particular genotype combination can be the product of thesusceptibility values for the genotype at each locus. If thesusceptibility presented is the relative susceptibility for a person, ora specific genotype for a person, compared to a reference population,then the combined susceptibility can be the product of the locusspecific susceptibility values and can correspond to an overallsusceptibility estimate compared with a population. If thesusceptibility for a person is based on a comparison to non-carriers ofthe at-risk allele, then the combined susceptibility can correspond toan estimate that compares the person with a given combination ofgenotypes at all loci to a group of individuals who do not carry at-riskvariants at any of those loci. The group of non-carriers of any at-riskvariant can have the lowest estimated susceptibility and can have acombined susceptibility, compared with itself, for example,non-carriers, of 1.0, but can have an overall susceptibility, comparedwith the population, of less than 1.0.

Overall risk for multiple risk variants can be performed using standardmethodology. Genetic variations described herein can form the basis ofrisk analysis that combines other genetic variations known to increaserisk of PML, or other genetic risk variants for PML. In certainembodiments of the disclosure, a plurality of variants (geneticvariations, variant alleles, and/or haplotypes) can be used for overallrisk assessment. These variants are in some embodiments selected fromthe genetic variations as disclosed herein. Other embodiments includethe use of the variants of the present disclosure in combination withother variants known to be useful for screening a susceptibility to PML.In such embodiments, the genotype status of a plurality of geneticvariations, markers and/or haplotypes is determined in an individual,and the status of the individual compared with the population frequencyof the associated variants, or the frequency of the variants inclinically healthy subjects, such as age-matched and sex-matchedsubjects.

Methods such as the use of available algorithms and software can be usedto identify, or call, significant genetic variations, including but notlimited to, algorithms of DNA Analytics or DNAcopy, iPattern and/orQuantiSNP. In some embodiments, a threshold logratio value can be usedto determine losses and gains. For example, using DNA Analytics, a log₂ratio cutoff of ≥0.5 and ≤0.5 to classify CNV gains and lossesrespectively can be used. For example, using DNA Analytics, a log₂ ratiocutoff of ≥0.25 and ≤0.25 to classify CNV gains and losses respectivelycan be used. As a further example, using DNAcopy, a log₂ ratio cutoff of≥0.35 and ≤0.35 to classify CNV gains and losses respectively can beused. For example, an Aberration Detection Module 2 (ADM2) algorithm,such as that of DNA Analytics 4.0.85 can be used to identify, or call,significant genetic variations. In some embodiments, two or morealgorithms can be used to identify, or call, significant geneticvariations. For example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or morealgorithms can be used to identify, or call, significant geneticvariations. In another embodiment, the log 2 ratio of one or moreindividual probes on a microarray can be used to identify significantgenetic variations, such as the presence of homozygously deleted regionsin a subject's genome. In some embodiments, significant geneticvariations can be CNVs.

CNVs detected by two or more algorithms can be defined as stringent andcan be utilized for further analyses. In some embodiments, theinformation and calls from two or more of the methods described hereincan be compared to each other to identify significant genetic variationsmore or less stringently. For example, CNV calls generated by two ormore of DNA Analytics, Aberration Detection Module 2 (ADM2) algorithms,and DNAcopy algorithms can be defined as stringent CNVs. In someembodiments significant or stringent genetic variations can be tagged asidentified or called if it can be found to have a minimal reciprocaloverlap to a genetic variation detected by one or more platforms and/ormethods described herein. For example, a minimum of 50% reciprocaloverlap can be used to tag the CNVs as identified or called. Forexample, significant or stringent genetic variations can be tagged asidentified or called if it can be found to have a reciprocal overlap ofmore than about 50%, 55% 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, 99%,or equal to 100%, to a genetic variation detected by one or moreplatforms and/or methods described herein. For example, significant orstringent genetic variations can be tagged as identified or called if itcan be found to have a reciprocal overlap of more than about 50%reciprocal overlap to a genetic variation detected by one or moreplatforms and/or methods described herein. In another embodiment,genetic variations can be detected from the log 2 ratio valuescalculated for individual probes present on an aCGH microarray via astatistical comparison of the probe's log 2 ratio value in a cohort ofsubjects with PML to the probe's log 2 ratio value in a cohort ofsubjects without PML.

In some embodiments, a threshold log ratio value can be used todetermine losses and gains. A log ratio value can be any log ratiovalue; for example, a log ratio value can be a log 2 ratio or a log 10ratio. In some embodiments, a CNV segment whose median log 2 ratio isless than or equal to a log 2 ratio threshold value can be classified asa loss. For example, any segment whose median log 2 ratio is less thanor equal to −0.1, −0.11, −0.12, −0.13, −0.14, −0.15, −0.16, −0.17,−0.18, −0.19, −0.2, −0.21, −0.22, −0.23, −0.24, −0.25, −0.26, −0.27,−0.28, −0.29, −0.3, −0.31, −0.32, −0.33, −0.34, −0.35, −0.36, −0.37,−0.38, −0.39, −0.4, −0.41, −0.42, −0.43, −0.44, −0.45, −0.46, −0.47,−0.48, −0.49, −0.5, −0.55, −0.6, −0.65, −0.7, −0.75, −0.8, −0.85, −0.9,−0.95, −1, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8, −1.9, −2,−2.1, −2.2, −2.3, −2.4, −2.5, −2.6, −2.7, −2.8, −2.9, −3, −3.1, −3.2,−3.3, −3.4, −3.5, −3.6, −3.7, −3.8, −3.9, −4, −4.1, −4.2, −4.3, −4.4,−4.5, −4.6, −4.7, −4.8, −4.9, −5, −5.5, −6, −6.5, −7, −7.5, −8, −8.5,−9, −9.5, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19, −20 or less,can be classified as a loss.

In some embodiments, one algorithm can be used to call or identifysignificant genetic variations, wherein any segment whose median log 2ratio was less than or equal to −0.1, −0.11, −0.12, −0.13, −0.14, −0.15,−0.16, −0.17, −0.18, −0.19, −0.2, −0.21, −0.22, −0.23, −0.24, −0.25,−0.26, −0.27, −0.28, −0.29, −0.3, −0.31, −0.32, −0.33, −0.34, −0.35,−0.36, −0.37, −0.38, −0.39, −0.4, −0.41, −0.42, −0.43, −0.44, −0.45,−0.46, −0.47, −0.48, −0.49, −0.5, −0.55, −0.6, −0.65, −0.7, −0.75, −0.8,−0.85, −0.9, −0.95, −1, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8,−1.9, −2, −2.1, −2.2, −2.3, −2.4, −2.5, −2.6, −2.7, −2.8, −2.9, −3,−3.1, −3.2, −3.3, −3.4, −3.5, −3.6, −3.7, −3.8, −3.9, −4, −4.1, −4.2,−4.3, −4.4, −4.5, −4.6, −4.7, −4.8, −4.9, −5, −5.5, −6, −6.5, −7, −7.5,−8, −8.5, −9, −9.5, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19,−20 or less, can be classified as a loss. For example, any CNV segmentwhose median log 2 ratio is less than −0.35 as determined by DNAcopy canbe classified as a loss. For example, losses can be determined accordingto a threshold log 2 ratio, which can be set at −0.35. In anotherembodiment, losses can be determined according to a threshold log 2ratio, which can be set at −0.5.

In some embodiments, two algorithms can be used to call or identifysignificant genetic variations, wherein any segment whose median log 2ratio is less than or equal to −0.1, −0.11, −0.12, −0.13, −0.14, −0.15,−0.16, −0.17, −0.18, −0.19, −0.2, −0.21, −0.22, −0.23, −0.24, −0.25,−0.26, −0.27, −0.28, −0.29, −0.3, −0.31, −0.32, −0.33, −0.34, −0.35,−0.36, −0.37, −0.38, −0.39, −0.4, −0.41, −0.42, −0.43, −0.44, −0.45,−0.46, −0.47, −0.48, −0.49, −0.5, −0.55, −0.6, −0.65, −0.7, −0.75, −0.8,−0.85, −0.9, −0.95, −1, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8,−1.9, −2, −2.1, −2.2, −2.3, −2.4, −2.5, −2.6, −2.7, −2.8, −2.9, −3,−3.1, −3.2, −3.3, −3.4, −3.5, −3.6, −3.7, −3.8, −3.9, −4, −4.1, −4.2,−4.3, −4.4, −4.5, −4.6, −4.7, −4.8, −4.9, −5, −5.5, −6, −6.5, −7, −7.5,−8, −8.5, −9, −9.5, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19,−20 or less, as determined by one algorithm, and wherein any segmentwhose median log 2 ratio is less than or equal to −0.1, −0.11, −0.12,−0.13, −0.14, −0.15, −0.16, −0.17, −0.18, −0.19, −0.2, −0.21, −0.22,−0.23, −0.24, −0.25, −0.26, −0.27, −0.28, −0.29, −0.3, −0.31, −0.32,−0.33, −0.34, −0.35, −0.36, −0.37, −0.38, −0.39, −0.4, −0.41, −0.42,−0.43, −0.44, −0.45, −0.46, −0.47, −0.48, −0.49, −0.5, −0.55, −0.6,−0.65, −0.7, −0.75, −0.8, −0.85, −0.9, −0.95, −1, −1.1, −1.2, −1.3,−1.4, −1.5, −1.6, −1.7, −1.8, −1.9, −2, −2.1, −2.2, −2.3, −2.4, −2.5,−2.6, −2.7, −2.8, −2.9, −3, −3.1, −3.2, −3.3, −3.4, −3.5, −3.6, −3.7,−3.8, −3.9, −4, −4.1, −4.2, −4.3, −4.4, −4.5, −4.6, −4.7, −4.8, −4.9,−5, −5.5, −6, −6.5, −7, −7.5, −8, −8.5, −9, −9.5, −10, −11, −12, −13,−14, −15, −16, −17, −18, −19, −20, or less, as determined by the otheralgorithm can be classified as a loss. For example, CNV calling cancomprise using the Aberration Detection Module 2 (ADM2) algorithm andthe DNAcopy algorithm, wherein losses can be determined according to atwo threshold log 2 ratios, wherein the Aberration Detection Module 2(ADM2) algorithm log 2 ratio can be −0.25 and the DNAcopy algorithm log2 ratio can be −0.41.

In some embodiments, the use of two algorithms to call or identifysignificant genetic variations can be a stringent method. In someembodiments, the use of two algorithms to call or identify significantgenetic variations can be a more stringent method compared to the use ofone algorithm to call or identify significant genetic variations.

In some embodiments, any CNV segment whose median log 2 ratio is greaterthan a log 2 ratio threshold value can be classified as a gain. Forexample, any segment whose median log 2 ratio is greater than 0.1, 0.11,0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23,0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35,0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47,0.48, 0.49, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1,1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3, or more can be classified as a gain.

In some embodiments, one algorithm can be used to call or identifysignificant genetic variations, wherein any segment whose median log 2ratio is greater than or equal to 0.1, 0.11, 0.12, 0.13, 0.14, 0.15,0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27,0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39,0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.55,0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3,or more can be classified as a gain. For example, any CNV segment whosemedian log 2 ratio is greater than 0.35 as determined by DNAcopy can beclassified as a gain. For example, gains can be determined according toa threshold log 2 ratio, which can be set at 0.35. In anotherembodiment, gains can be determined according to a threshold log 2ratio, which can be set at 0.5.

In some embodiments, two algorithms can be used to call or identifysignificant genetic variations, wherein any segment whose median log 2ratio is greater than or equal to 0.1, 0.11, 0.12, 0.13, 0.14, 0.15,0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27,0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39,0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.55,0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3 ormore, as determined by one algorithm, and wherein any segment whosemedian log 2 ratio is greater than or equal to 0.1, 0.11, 0.12, 0.13,0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25,0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37,0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49,or 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3, or more, as determined by the other algorithm the can beclassified as a gain. For example, CNV calling can comprise using theAberration Detection Module 2 (ADM2) algorithm and the DNAcopyalgorithm, wherein gains can be determined according to a two thresholdlog 2 ratios, wherein the Aberration Detection Module 2 (ADM2) algorithmlog 2 ratio can be 0.25 and the DNAcopy algorithm log 2 ratio can be0.32.

Any CNV segment whose absolute (median log-ratio/mad) value is less than2 can be excluded (not identified as a significant genetic variation).For example, any CNV segment whose absolute (median log-ratio/mad) valueis less than 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9,0.8, 0.7, 0.6, or 0.5 or less can be excluded.

In some embodiments, multivariate analyses or joint risk analyses,including the use of multiplicative model for overall risk assessment,can subsequently be used to determine the overall risk conferred basedon the genotype status at the multiple loci. Use of a multiplicativemodel, for example, assuming that the risk of individual risk variantsmultiply to establish the overall effect, allows for a straight-forwardcalculation of the overall risk for multiple markers. The multiplicativemodel is a parsimonious model that usually fits the data of complextraits reasonably well. Deviations from multiplicity have been rarelydescribed in the context of common variants for common diseases, and ifreported are usually only suggestive since very large sample sizes canbe required to be able to demonstrate statistical interactions betweenloci. Assessment of risk based on such analysis can subsequently be usedin the methods, uses and kits of the disclosure, as described herein.

In some embodiments, the significance of increased or decreasedsusceptibility can be measured by a percentage. In some embodiments, asignificant increased susceptibility can be measured as a relativesusceptibility of at least 1.2, including but not limited to: at least1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least1.8, at least 1.9, at least 2.0, at least 2.5, at least 3.0, at least4.0, at least 5.0, at least 6.0, at least 7.0, at least 8.0, at least9.0, at least 10.0, and at least 15.0. In some embodiments, a relativesusceptibility of at least 2.0, at least 3.0, at least 4.0, at least,5.0, at least 6.0, or at least 10.0 is significant. Other values forsignificant susceptibility are also contemplated, for example, at least2.5, 3.5, 4.5, 5.5, or any suitable other numerical values, wherein thevalues are also within scope of the present disclosure. In someembodiments, a significant increase in susceptibility is at least about20%, including but not limited to about 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%,400%, 500%, 600%, 700%, 800%, 900%, 1000%, and 1500%. In one particularembodiment, a significant increase in susceptibility is at least 100%.In other embodiments, a significant increase in susceptibility is atleast 200%, at least 300%, at least 400%, at least 500%, at least 700%,at least 800%, at least 900% and at least 1000%. Other cutoffs or rangesas deemed suitable by the person skilled in the art to characterize thedisclosure are also contemplated, and those are also within scope of thepresent disclosure. In certain embodiments, a significant increase insusceptibility is characterized by a p-value, such as a p-value of lessthan 0.5, less than 0.4, less than 0.3, less than 0.2, less than 0.1,less than 0.05, less than 0.01, less than 0.001, less than 0.0001, lessthan 0.00001, less than 0.000001, less than 0.0000001, less than0.00000001, or less than 0.000000001.

In some embodiments, an individual who is at a decreased susceptibilityfor or the lack of presence of a condition (e.g., PML) can be anindividual in whom at least one genetic variation, conferring decreasedsusceptibility for or the lack of presence of the condition isidentified. In some embodiments, the genetic variations conferringdecreased susceptibility are also protective. In one aspect, the geneticvariations can confer a significant decreased susceptibility of or lackof presence of PML.

In some embodiments, significant decreased susceptibility can bemeasured as a relative susceptibility of less than 0.9, including butnot limited to less than 0.9, less than 0.8, less than 0.7, less than0.6, less than 0.5, less than 0.4, less than 0.3, less than 0.2 and lessthan 0.1. In some embodiments, the decrease in susceptibility is atleast 20%, including but not limited to at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95% and at least 98%. Other cutoffs orranges as deemed suitable by the person, skilled in the art tocharacterize the disclosure are however also contemplated, and those arealso within scope of the present disclosure. In certain embodiments, asignificant decrease in susceptibility is characterized by a p-value,such as a p-value of less than 0.05, less than 0.01, less than 0.001,less than 0.0001, less than 0.00001, less than 0.000001, less than0.0000001, less than 0.00000001, or less than 0.000000001. Other testsfor significance can be used, for example, a Fisher-exact test. Otherstatistical tests of significance known to the skilled person are alsocontemplated and are also within scope of the disclosure.

In some preferred embodiments, the significance of increased ordecreased susceptibility can be determined according to the ratio ofmeasurements from a test subject to a reference subject. In someembodiments, losses or gains of one or more CNVs can be determinedaccording to a threshold log₂ ratio determined by these measurements. Insome embodiments, a log₂ ratio value greater than 0.35, or 0.5, isindicative of a gain of one or more CNVs. In some embodiments, a log₂ratio value less than −0.35, or −0.5, is indicative of a loss of one ormore CNVs. In some embodiments, the ratio of measurements from a testsubject to a reference subject may be inverted such that the log 2ratios of copy number gains are negative and the log 2 ratios of copynumber losses are positive.

In some embodiments, the combined or overall susceptibility associatedwith a plurality of variants associated with PML can also be assessed;for example, the genetic variations described herein to be associatedwith susceptibility to PML can be combined with other common geneticrisk factors. Combined risk for such genetic variants can be estimatedin an analogous fashion to the methods described herein.

Calculating risk conferred by a particular genotype for the individualcan be based on comparing the genotype of the individual to previouslydetermined risk expressed, for example, as a relative risk (RR) or anodds ratio (OR), for the genotype, for example, for a heterozygouscarrier of an at-risk variant for PML. An odds ratio can be astatistical measure used as a metric of causality. For example, ingenetic disease research it can be used to convey the significance of avariant in a disease cohort relative to an unaffected/normal cohort. Thecalculated risk for the individual can be the relative risk for asubject, or for a specific genotype of a subject, compared to theaverage population. The average population risk can be expressed as aweighted average of the risks of different genotypes, using results froma reference population, and the appropriate calculations to calculatethe risk of a genotype group relative to the population can then beperformed. Alternatively, the risk for an individual can be based on acomparison of particular genotypes, for example, heterozygous and/orhomozygous carriers of an at-risk allele of a marker compared withnon-carriers of the at-risk allele (or pair of alleles in the instanceof compound heterozygous variants, wherein one variant impacts thematernally inherited allele and the other impacts the paternallyinherited allele). Using the population average can, in certainembodiments, be more convenient, since it provides a measure that can beeasy to interpret for the user, for example, a measure that gives therisk for the individual, based on his/her genotype, compared with theaverage in the population.

In some embodiments, the OR value can be calculated as follows:OR=(A/(N1−A))/(U/(N2−U)), where A=number of affected cases with variant,N1=total number of affected cases, U=number of unaffected cases withvariant and N2=total number of unaffected cases. In circumstances whereU=0, it is conventional to set U=1, so as to avoid infinities. In somepreferred embodiments, the OR can be calculated essentially as above,except that where U or A=0, 0.5 is added to all of A, N1, U, N2. Inanother embodiment, a Fisher's Exact Test (FET) can be calculated usingstandard methods. In another embodiment, the p-values can be correctedfor false discovery rate (FDR) using the Benjamini-Hochberg method(Benjamini Y. and Hochberg Y., J. Royal Statistical Society 57:289(1995); Osborne J. A. and Barker C. A. (2007)).

In certain embodiments of the disclosure, a genetic variation iscorrelated to PML by referencing genetic variation data to a look-uptable that comprises correlations between the genetic variation and PML.The genetic variation in certain embodiments comprises at least oneindication of the genetic variation. In some embodiments, the tablecomprises a correlation for one genetic variation. In other embodiments,the table comprises a correlation for a plurality of genetic variationsin both scenarios, by referencing to a look-up table that gives anindication of a correlation between a genetic variation and PML, a riskfor PML, or a susceptibility to PML, can be identified in the individualfrom whom the nucleic acid sample is derived.

The present disclosure also pertains to methods of clinical screening,for example, diagnosis, prognosis, or theranosis of a subject performedby a medical professional using the methods disclosed herein. In otherembodiments, the disclosure pertains to methods of screening performedby a layman. The layman can be a customer of a genotyping, microarray,exome sequencing, or whole genome sequencing service provider. Thelayman can also be a genotype, microarray, exome sequencing, or wholegenome sequencing service provider, who performs genetic analysis on aDNA sample from an individual, in order to provide service related togenetic risk factors for particular traits or diseases, based on thegenotype status of the subject obtained from use of the methodsdescribed herein. The resulting genotype or genetic information can bemade available to the individual and can be compared to informationabout PML or risk of developing PML associated with one or variousgenetic variations, including but not limited to, information frompublic or private genetic variation databases or literature andscientific publications. The screening applications of PML-associatedgenetic variations, as described herein, can, for example, be performedby an individual, a health professional, or a third party, for example aservice provider who interprets genotype information from the subject.In some embodiments the genetic analysis is performed in aCLIA-certified laboratory (e.g. the federal regulatory standards theU.S. that are specified in the Clinical Laboratory ImprovementAmendments, administered by the Centers for Medicare and MedicaidServices) or equivalent laboratories in Europe and elsewhere in theworld.

The information derived from analyzing sequence data can be communicatedto any particular body, including the individual from which the nucleicacid sample or sequence data is derived, a guardian or representative ofthe individual, clinician, research professional, medical professional,service provider, and medical insurer or insurance company. Medicalprofessionals can be, for example, doctors, nurses, medical laboratorytechnologists, and pharmacists. Research professionals can be, forexample, principle investigators, research technicians, postdoctoraltrainees, and graduate students.

In some embodiments, a professional can be assisted by determiningwhether specific genetic variants are present in a nucleic acid samplefrom a subject, and communicating information about genetic variants toa professional. After information about specific genetic variants isreported, a medical professional can take one or more actions that canaffect subject care. For example, a medical professional can recordinformation in the subject's medical record (e.g., electronic healthrecord or electronic medical record, including, but not limited to,country-scale health services such as the National Health Service in theUnited Kingdom) regarding the subject's risk of developing PML. In someembodiments, a medical professional can record information regardingrisk assessment, or otherwise transform the subject's medical record, toreflect the subject's current medical condition. In some embodiments, amedical professional can review and evaluate a subject's entire medicalrecord and assess multiple treatment strategies for clinicalintervention of a subject's condition. In another embodiment,information can be recorded in the context of the system developed bythe World Health Organization (WHO), the International StatisticalClassification of Diseases and Related Health Problems (ICD), which iscurrently using the 10th revision (ICD-10 codes). For example, theICD-10 code for PML is A81.2, whereas the ICD-10 code for multiplesclerosis is G35.

A medical professional can initiate or modify treatment after receivinginformation regarding a subject's screening for PML, for example. Insome embodiments, a medical professional can recommend a change intherapy or exclude a therapy. In some embodiments, a medicalprofessional can enroll a subject in a clinical trial for, by way ofexample, detecting correlations between a haplotype as described hereinand any measurable or quantifiable parameter relating to the outcome ofthe treatment as described above.

In some embodiments, a medical professional can communicate informationregarding a subject's screening of developing PML to a subject or asubject's family. In some embodiments, a medical professional canprovide a subject and/or a subject's family with information regardingPML and risk assessment information, including treatment options, andreferrals to specialists. In some embodiments, a medical professionalcan provide a copy of a subject's medical records to a specialist. Insome embodiments, a research professional can apply informationregarding a subject's risk of developing PML to advance scientificresearch. In some embodiments, a research professional can obtain asubject's haplotype as described herein to evaluate a subject'senrollment, or continued participation, in a research study or clinicaltrial. In some embodiments, a research professional can communicateinformation regarding a subject's screening of PML to a medicalprofessional. In some embodiments, a research professional can refer asubject to a medical professional.

Any appropriate method can be used to communicate information to anotherperson. For example, information can be given directly or indirectly toa professional and a laboratory technician can input a subject's geneticvariation as described herein into a computer-based record. In someembodiments, information is communicated by making a physical alterationto medical or research records. For example, a medical professional canmake a permanent notation or flag a medical record for communicating therisk assessment to other medical professionals reviewing the record. Inaddition, any type of communication can be used to communicate the riskassessment information. For example, mail, e-mail, telephone, andface-to-face interactions can be used. The information also can becommunicated to a professional by making that information electronicallyavailable to the professional. For example, the information can becommunicated to a professional by placing the information on a computerdatabase such that the professional can access the information. Inaddition, the information can be communicated to a hospital, clinic, orresearch facility serving as an agent for the professional.

Results of these tests, and optionally interpretive information, can bereturned to the subject, the health care provider or to a third party.The results can be communicated to the tested subject, for example, witha prognosis and optionally interpretive materials that can help thesubject understand the test results and prognosis; used by a health careprovider, for example, to determine whether to administer a specificdrug, or whether a subject should be assigned to a specific category,for example, a category associated with a specific diseaseendophenotype, or with drug response or non-response; used by a thirdparty such as a healthcare payer, for example, an insurance company orHMO, or other agency, to determine whether or not to reimburse a healthcare provider for services to the subject, or whether to approve theprovision of services to the subject. For example, the healthcare payercan decide to reimburse a health care provider for treatments for PML ifthe subject has PML or has an increased risk of developing PML.

Also provided herein are databases that include a list of geneticvariations as described herein, and wherein the list can be largely orentirely limited to genetic variations identified as useful forscreening PML as described herein. The list can be stored, for example,on a flat file or computer-readable medium. The databases can furtherinclude information regarding one or more subjects, for example, whethera subject is affected or unaffected, clinical information such asendophenotype, age of onset of symptoms, any treatments administered andoutcomes, for example, data relevant to pharmacogenomics, diagnostics,prognostics or theranostics, and other details, for example, data aboutthe disorder in the subject, or environmental (e.g., including, but notlimited to, infection or a history of infection with HIV or JCV) orother genetic factors. The databases can be used to detect correlationsbetween a particular haplotype and the information regarding thesubject.

The methods described herein can also include the generation of reportsfor use, for example, by a subject, care giver, or researcher, thatinclude information regarding a subject's genetic variations, andoptionally further information such as treatments administered,treatment history, medical history, predicted response, and actualresponse. The reports can be recorded in a tangible medium, e.g., acomputer-readable disk, a solid state memory device, or an opticalstorage device.

Methods of Screening Using Variations in RNA and/or Polypeptides

In some embodiments of the disclosure, screening of PML can be made byexamining or comparing changes in expression, localization, bindingpartners, and composition of a polypeptide encoded by a nucleic acidvariant associated with PML, for example, in those instances where thegenetic variations of the present disclosure results in a change in thecomposition or expression of the polypeptide and/or RNA, for example,mRNAs, microRNAs (miRNAs), and other noncoding RNAs (ncRNAs). Thus,screening of PML can be made by examining expression and/or compositionof one of these polypeptides and/or RNA, or another polypeptide and/orRNA encoded by a nucleic acid associated with PML, in those instanceswhere the genetic variation of the present disclosure results in achange in the expression, localization, binding partners, and/orcomposition of the polypeptide and/or RNA. In some embodiments,screening can comprise diagnosing a subject. In some embodiments,screening can comprise determining a prognosis of a subject, for exampledetermining the susceptibility of developing PML. In some embodiments,screening can comprise theranosing a subject.

The genetic variations described herein that show association to PML canplay a role through their effect on one or more of these genes, eitherby directly impacting one or more genes or influencing the expression ofone or more nearby genes. For example, while not intending to be limitedby theory, it is generally expected that a deletion of a chromosomalsegment comprising a particular gene, or a fragment of a gene, caneither result in an altered composition or expression, or both, of theencoded polypeptide and/or mRNA. Likewise, duplications, or high numbercopy number variations, are in general expected to result in increasedexpression of encoded polypeptide and/or RNA if the gene they areexpressed from is fully encompassed within the duplicated (ortriplicated, or even higher copy number gains) genomic segment, orconversely can result in decreased expression or a disrupted RNA orpolypeptide if one or both breakpoints of the copy number gain disrupt agiven gene. Other possible mechanisms affecting genes within a geneticvariation region include, for example, effects on transcription, effectson RNA splicing, alterations in relative amounts of alternative spliceforms of mRNA, effects on RNA stability, effects on transport from thenucleus to cytoplasm, and effects on the efficiency and accuracy oftranslation. Thus, DNA variations can be detected directly, using thesubjects unamplified or amplified genomic DNA, or indirectly, using RNAor DNA obtained from the subject's tissue(s) that are present in anaberrant form or expression level as a result of the genetic variationsof the disclosure showing association to PML. In another embodiment, DNAvariations can be detected indirectly using a polypeptide or proteinobtained from the subject's tissue(s) that is present in an aberrantform or expression level as a result of genetic variations of thedisclosure showing association to the PML. In another embodiment, anaberrant form or expression level of a polypeptide or protein thatresults from one or more genetic variations of the disclosure showingassociation to PML can be detected indirectly via another polypeptide orprotein present in the same biological/cellular pathway that ismodulated or interacts with said polypeptide or protein that resultsfrom one or more genetic variations of the disclosure. In someembodiments, the genetic variations of the disclosure showingassociation to PML can affect the expression of a gene within thegenetic variation region. In some embodiments, a genetic variationaffecting an exonic region of a gene can affect, disrupt, or modulatethe expression of the gene. In some embodiments, a genetic variationaffecting an intronic or intergenic region of a gene can affect,disrupt, or modulate the expression of the gene.

Certain genetic variation regions can have flanking duplicated segments,and genes within such segments can have altered expression and/orcomposition as a result of such genomic alterations. Regulatory elementsaffecting gene expression can be located far away, even as far as tensor hundreds of kilobases away, from the gene that is regulated by saidregulatory elements. Thus, in some embodiments, regulatory elements forgenes that are located outside the gene (e.g., upstream or downstream ofthe gene) can be located within the genetic variation, and thus beaffected by the genetic variation. It is thus contemplated that thedetection of the genetic variations described herein, can be used forassessing expression for one or more of associated genes not directlyimpacted by the genetic variations. In some embodiments, a geneticvariation affecting an intergenic region of a gene can affect, disrupt,or modulate the expression of a gene located elsewhere in the genome,such as described above. For example, a genetic variation affecting anintergenic region of a gene can affect, disrupt, or modulate theexpression of a transcription factor, located elsewhere in the genome,which regulates the gene. Regulatory elements can also be located withina gene, such as within intronic regions, and similarly impact theexpression level of the gene and ultimately the protein expression levelwithout changing the structure of the protein. The effects of geneticvariants on regulatory elements can manifest in a tissue-specificmanner; for example, one or more transcription factors that bind to theregulatory element that is impacted by one or more genetic variationsmay be expressed at higher concentration in neurons as compared to skincells (e.g., the impact of the one or more genetic variations may beprimarily evident in neuronal cells).

In some embodiments, genetic variations of the disclosure showingassociation to PML can affect protein expression at the translationallevel. It can be appreciated by those skilled in the art that this canoccur by increased or decreased expression of one or more microRNAs(miRNAs) that regulates expression of a protein known to be important,or implicated, in the cause, onset, or progression of PML. Increased ordecreased expression of the one or more miRNAs can result from gain orloss of the whole miRNA gene, disruption or impairment of a portion ofthe gene (e.g., by an indel or CNV), or even a single base change (SNPor SNV) that produces an altered, non-functional or aberrant functioningmiRNA sequence. It can also be appreciated by those skilled in the artthat the expression of protein, for example, one known to cause PML byincreased or decreased expression, can result due to a genetic variationthat results in alteration of an existing miRNA binding site within thepolypeptide's mRNA transcript, or even creates a new miRNA binding sitethat leads to aberrant polypeptide expression.

A variety of methods can be used for detecting polypeptide compositionand/or expression levels, including but not limited to enzyme linkedimmunosorbent assays (ELISA), Western blots, spectroscopy, massspectrometry, peptide arrays, colorimetry, electrophoresis, isoelectricfocusing, immunoprecipitations, immunoassays, and immunofluorescence andother methods well-known in the art. A test nucleic acid sample from asubject can be assessed for the presence of an alteration in theexpression and/or an alteration in composition of the polypeptideencoded by a nucleic acid associated with PML. An “alteration” in thepolypeptide expression or composition, as used herein, refers to analteration in expression or composition in a test nucleic acid sample,as compared to the expression or composition of the polypeptide in acontrol nucleic acid sample. Such alteration can, for example, be analteration in the quantitative polypeptide expression or can be analteration in the qualitative polypeptide expression, for example,expression of a mutant polypeptide or of a different splicing variant,or a combination thereof. In some embodiments, screening of PML can bemade by detecting a particular splicing variant encoded by a nucleicacid associated with PML, or a particular pattern of splicing variants.

Antibodies can be polyclonal or monoclonal and can be labeled orunlabeled. An intact antibody or a fragment thereof can be used. Theterm “labeled”, with regard to the probe or antibody, is intended toencompass direct labeling of the probe or antibody by coupling adetectable substance to the probe or antibody, as well as indirectlabeling of the probe or antibody by reactivity with another reagentthat is directly labeled as previously described herein. Othernon-limiting examples of indirect labeling include detection of aprimary antibody using a labeled secondary antibody, for example, afluorescently-labeled secondary antibody and end-labeling of a DNA probewith biotin such that it can be detected with fluorescently-labeledstreptavidin.

Methods of Detecting Genetic Variations

In some embodiments, standard techniques for genotyping for the presencegenetic variations, for example, amplification, can be used.Amplification of nucleic acids can be accomplished using methods knownin the art. Generally, sequence information from the region of interestcan be used to design oligonucleotide primers that can be identical orsimilar in sequence to opposite strands of a template to be amplified.In some embodiments, amplification methods can include but are notlimited to, fluorescence-based techniques utilizing PCR, for example,ligase chain reaction (LCR), Nested PCR, transcription amplification,self-sustained sequence replication, nucleic acid based sequenceamplification (NASBA), and multiplex ligation-dependent probeamplification (MLPA). Guidelines for selecting primers for PCRamplification are well known in the art. In some embodiments, a computerprogram can be used to design primers, for example, Oligo (NationalBiosciences, Inc, Plymouth Minn.), MacVector (Kodak/IBI), and GCG suiteof sequence analysis programs.

In some embodiments, commercial methodologies available for genotyping,for example, SNP genotyping, can be used, but are not limited to, TaqMangenotyping assays (Applied Biosystems), SNPlex platforms (AppliedBiosystems), gel electrophoresis, capillary electrophoresis, sizeexclusion chromatography, mass spectrometry, for example, MassARRAYsystem (Sequenom), minisequencing methods, real-time Polymerase ChainReaction (PCR), Bio-Plex system (BioRad), CEQ and SNPstream systems(Beckman), array hybridization technology, for example, AffymetrixGeneChip (Perlegen), BeadArray Technologies, for example, IlluminaGoldenGate and Infinium assays, array tag technology, MultiplexLigation-dependent Probe Amplification (MLPA), and endonuclease-basedfluorescence hybridization technology (Invader assay, either usingunamplified or amplified genomic DNA, or unamplified total RNA, orunamplified or amplified cDNA; Third Wave/Hologic). PCR can be aprocedure in which target nucleic acid is amplified in a manner similarto that described in U.S. Pat. No. 4,683,195 and subsequentmodifications of the procedure described therein. PCR can include athree phase temperature cycle of denaturation of DNA into singlestrands, annealing of primers to the denatured strands, and extension ofthe primers by a thermostable DNA polymerase enzyme. This cycle can berepeated so that there are enough copies to be detected and analyzed. Insome embodiments, real-time quantitative PCR can be used to determinegenetic variations, wherein quantitative PCR can permit both detectionand quantification of a DNA sequence in a nucleic acid sample, forexample, as an absolute number of copies or as a relative amount whennormalized to DNA input or other normalizing genes. In some embodiments,methods of quantification can include the use of fluorescent dyes thatcan intercalate with double-stranded DNA, and modified DNAoligonucleotide probes that can fluoresce when hybridized with acomplementary DNA.

In some embodiments of the disclosure, a nucleic acid sample obtainedfrom the subject can be collected and PCR can be used to amplify afragment of nucleic acid that comprises one or more genetic variationsthat can be indicative of a susceptibility to PML. In some embodiments,detection of genetic variations can be accomplished by expressionanalysis, for example, by using quantitative PCR. In some embodiments,this technique can assess the presence or absence of a geneticalteration in the expression or composition of one or more polypeptidesor splicing variants encoded by a nucleic acid associated with PML.

In some embodiments, the nucleic acid sample from a subject containing aSNP can be amplified by PCR prior to detection with a probe. In such anembodiment, the amplified DNA serves as the template for a detectionprobe and, in some embodiments, an enhancer probe. Certain embodimentsof the detection probe, the enhancer probe, and/or the primers used foramplification of the template by PCR can comprise the use of modifiedbases, for example, modified A, T, C, G, and U, wherein the use ofmodified bases can be useful for adjusting the melting temperature ofthe nucleotide probe and/or primer to the template DNA, In someembodiments, modified bases are used in the design of the detectionnucleotide probe. Any modified base known to the skilled person can beselected in these methods, and the selection of suitable bases is wellwithin the scope of the skilled person based on the teachings herein andknown bases available from commercial sources as known to the skilledperson.

In some embodiments, identification of genetic variations can beaccomplished using hybridization methods. The presence of a specificmarker allele or a particular genomic segment comprising a geneticvariation, or representative of a genetic variation, can be indicated bysequence-specific hybridization of a nucleic acid probe specific for theparticular allele or the genetic variation in a nucleic acid sample thathas or has not been amplified but methods described herein. The presenceof more than one specific marker allele or several genetic variationscan be indicated by using two or more sequence-specific nucleic acidprobes, wherein each is specific for a particular allele and/or geneticvariation.

Hybridization can be performed by methods well known to the personskilled in the art, for example, hybridization techniques such asfluorescent in situ hybridization (FISH), Southern analysis, Northernanalysis, or in situ hybridization. In some embodiments, hybridizationrefers to specific hybridization, wherein hybridization can be performedwith no mismatches. Specific hybridization, if present, can be usingstandard methods. In some embodiments, if specific hybridization occursbetween a nucleic acid probe and the nucleic acid in the nucleic acidsample, the nucleic acid sample can contain a sequence that can becomplementary to a nucleotide present in the nucleic acid probe. In someembodiments, if a nucleic acid probe can contain a particular allele ofa polymorphic marker, or particular alleles for a plurality of markers,specific hybridization is indicative of the nucleic acid beingcompletely complementary to the nucleic acid probe, including theparticular alleles at polymorphic markers within the probe. In someembodiments a probe can contain more than one marker alleles of aparticular haplotype, for example, a probe can contain allelescomplementary to 2, 3, 4, 5 or all of the markers that make up aparticular haplotype. In some embodiments detection of one or moreparticular markers of the haplotype in the nucleic acid sample isindicative that the source of the nucleic acid sample has the particularhaplotype.

In some embodiments, PCR conditions and primers can be developed thatamplify a product only when the variant allele is present or only whenthe wild type allele is present, for example, allele-specific PCR. Insome embodiments of allele-specific PCR, a method utilizing a detectionoligonucleotide probe comprising a fluorescent moiety or group at its 3′terminus and a quencher at its 5′ terminus, and an enhanceroligonucleotide, can be employed (see e.g., Kutyavin et al., NucleicAcid Res. 34:e128 (2006)).

An allele-specific primer/probe can be an oligonucleotide that isspecific for particular a polymorphism can be prepared using standardmethods. In some embodiments, allele-specific oligonucleotide probes canspecifically hybridize to a nucleic acid region that contains a geneticvariation. In some embodiments, hybridization conditions can be selectedsuch that a nucleic acid probe can specifically bind to the sequence ofinterest, for example, the variant nucleic acid sequence.

In some embodiments, allele-specific restriction digest analysis can beused to detect the existence of a polymorphic variant of a polymorphism,if alternate polymorphic variants of the polymorphism can result in thecreation or elimination of a restriction site. Allele-specificrestriction digests can be performed, for example, with the particularrestriction enzyme that can differentiate the alleles. In someembodiments, PCR can be used to amplify a region comprising thepolymorphic site, and restriction fragment length polymorphism analysiscan be conducted. In some embodiments, for sequence variants that do notalter a common restriction site, mutagenic primers can be designed thatcan introduce one or more restriction sites when the variant allele ispresent or when the wild type allele is present.

In some embodiments, fluorescence polarization template-directeddye-terminator incorporation (FP-TDI) can be used to determine which ofmultiple polymorphic variants of a polymorphism can be present in asubject. Unlike the use of allele-specific probes or primers, thismethod can employ primers that can terminate adjacent to a polymorphicsite, so that extension of the primer by a single nucleotide can resultin incorporation of a nucleotide complementary to the polymorphicvariant at the polymorphic site.

In some embodiments, DNA containing an amplified portion can bedot-blotted, using standard methods and the blot contacted with theoligonucleotide probe. The presence of specific hybridization of theprobe to the DNA can then be detected. The methods can includedetermining the genotype of a subject with respect to both copies of thepolymorphic site present in the genome, wherein if multiple polymorphicvariants exist at a site, this can be appropriately indicated byspecifying which variants are present in a subject. Any of the detectionmeans described herein can be used to determine the genotype of asubject with respect to one or both copies of the polymorphism presentin the subject's genome.

In some embodiments, a peptide nucleic acid (PNA) probe can be used inaddition to, or instead of, a nucleic acid probe in the methodsdescribed herein. A PNA can be a DNA mimic having a peptide-like,inorganic backbone, for example, N-(2-aminoethyl) glycine units with anorganic base (A, G, C, T or U) attached to the glycine nitrogen via amethylene carbonyl linker.

Nucleic acid sequence analysis can also be used to detect geneticvariations, for example, genetic variations can be detected bysequencing exons, introns, 5′ untranslated sequences, or 3′ untranslatedsequences. One or more methods of nucleic acid analysis that areavailable to those skilled in the art can be used to detect geneticvariations, including but not limited to, direct manual sequencing,automated fluorescent sequencing, single-stranded conformationpolymorphism assays (SSCP); clamped denaturing gel electrophoresis(CDGE); denaturing gradient gel electrophoresis (DGGE), two-dimensionalgel electrophoresis (2DGE or TDGE); conformational sensitive gelelectrophoresis (CSGE); denaturing high performance liquidchromatography (DHPLC), infrared matrix-assisted laserdesorption/ionization (IR-MALDI) mass spectrometry, mobility shiftanalysis, quantitative real-time PCR, restriction enzyme analysis,heteroduplex analysis; chemical mismatch cleavage (CMC), RNaseprotection assays, use of polypeptides that recognize nucleotidemismatches, allele-specific PCR, real-time pyrophosphate DNA sequencing,PCR amplification in combination with denaturing high performance liquidchromatography (dHPLC), and combinations of such methods.

Sequencing can be accomplished through classic Sanger sequencingmethods, which are known in the art. In some embodiments sequencing canbe performed using high-throughput sequencing methods some of whichallow detection of a sequenced nucleotide immediately after or upon itsincorporation into a growing strand, for example, detection of sequencein substantially real time or real time. In some cases, high throughputsequencing generates at least 1,000, at least 5,000, at least 10,000, atleast 20,000, at least 30,000, at least 40,000, at least 50,000, atleast 100,000 or at least 500,000 sequence reads per hour; with eachread being at least 50, at least 60, at least 70, at least 80, at least90, at least 100, at least 120 or at least 150 bases per read (or500-1,000 bases per read for 454).

High-throughput sequencing methods can include but are not limited to,Massively Parallel Signature Sequencing (MPSS, Lynx Therapeutics),Polony sequencing, 454 pyrosequencing, Illumina (Solexa) sequencing,Illumina (Solexa) sequencing using 10× Genomics library preparation,SOLiD sequencing, on semiconductor sequencing, DNA nanoball sequencing,Helioscope™ single molecule sequencing, Single Molecule SMRT™sequencing, Single Molecule real time (RNAP) sequencing, Nanopore DNAsequencing, and/or sequencing by hybridization, for example, anon-enzymatic method that uses a DNA microarray, or microfluidic Sangersequencing.

In some embodiments, high-throughput sequencing can involve the use oftechnology available by Helicos BioSciences Corporation (Cambridge,Mass.) such as the Single Molecule Sequencing by Synthesis (SMSS)method. SMSS is unique because it allows for sequencing the entire humangenome in up to 24 hours. This fast sequencing method also allows fordetection of a SNP/nucleotide in a sequence in substantially real timeor real time. Finally, SMSS is powerful because, like the MIPtechnology, it does not use a pre-amplification step prior tohybridization. SMSS does not use any amplification. SMSS is described inUS Publication Application Nos. 20060024711; 20060024678; 20060012793;20060012784; and 20050100932. In some embodiments, high-throughputsequencing involves the use of technology available by 454 LifeSciences, Inc. (a Roche company, Branford, Conn.) such as thePicoTiterPlate device which includes a fiber optic plate that transmitschemiluminescent signal generated by the sequencing reaction to berecorded by a CCD camera in the instrument. This use of fiber opticsallows for the detection of a minimum of 20 million base pairs in 4.5hours.

In some embodiments, PCR-amplified single-strand nucleic acid can behybridized to a primer and incubated with a polymerase, ATP sulfurylase,luciferase, apyrase, and the substrates luciferin and adenosine 5′phosphosulfate. Next, deoxynucleotide triphosphates corresponding to thebases A, C, G, and T (U) can be added sequentially. A base incorporationcan be accompanied by release of pyrophosphate, which can be convertedto ATP by sulfurylase, which can drive synthesis of oxyluciferin and therelease of visible light. Since pyrophosphate release can be equimolarwith the number of incorporated bases, the light given off can beproportional to the number of nucleotides adding in any one step. Theprocess can repeat until the entire sequence can be determined. In someembodiments, pyrosequencing can be utilized to analyze amplicons todetermine whether breakpoints are present. In some embodiments,pyrosequencing can map surrounding sequences as an internal qualitycontrol.

Pyrosequencing analysis methods are known in the art. Sequence analysiscan include a four-color sequencing by ligation scheme (degenerateligation), which involves hybridizing an anchor primer to one of fourpositions. Then an enzymatic ligation reaction of the anchor primer to apopulation of degenerate nonamers that are labeled with fluorescent dyescan be performed. At any given cycle, the population of nonamers that isused can be structured such that the identity of one of its positionscan be correlated with the identity of the fluorophore attached to thatnonamer. To the extent that the ligase discriminates for complementarilyat that queried position, the fluorescent signal can allow the inferenceof the identity of the base. After performing the ligation andfour-color imaging, the anchor primer: nonamer complexes can be strippedand a new cycle begins. Methods to image sequence information afterperforming ligation are known in the art.

In some embodiments, analysis by restriction enzyme digestion can beused to detect a particular genetic variation if the genetic variationresults in creation or elimination of one or more restriction sitesrelative to a reference sequence. In some embodiments, restrictionfragment length polymorphism (RFLP) analysis can be conducted, whereinthe digestion pattern of the relevant DNA fragment indicates thepresence or absence of the particular genetic variation in the nucleicacid sample.

In some embodiments, arrays of oligonucleotide probes that can becomplementary to target nucleic acid sequence segments from a subjectcan be used to identify genetic variations. In some embodiments, anarray of oligonucleotide probes comprises an oligonucleotide array, forexample, a microarray. In some embodiments, the present disclosurefeatures arrays that include a substrate having a plurality ofaddressable areas, and methods of using them. At least one area of theplurality includes a nucleic acid probe that binds specifically to asequence comprising a genetic variation, and can be used to detect theabsence or presence of the genetic variation, for example, one or moreSNPs, microsatellites, or CNVs, as described herein, to determine oridentify an allele or genotype. For example, the array can include oneor more nucleic acid probes that can be used to detect a geneticvariation associated with a gene and/or gene product. In someembodiments, the array can further comprise at least one area thatincludes a nucleic acid probe that can be used to specifically detectanother marker associated with PML as described herein.

Microarray hybridization can be performed by hybridizing a nucleic acidof interest, for example, a nucleic acid encompassing a geneticvariation, with the array and detecting hybridization using nucleic acidprobes. In some embodiments, the nucleic acid of interest is amplifiedprior to hybridization. Hybridization and detecting can be carried outaccording to standard methods described in Published PCT Applications:WO 92/10092 and WO 95/11995, and U.S. Pat. No. 5,424,186. For example,an array can be scanned to determine the position on the array to whichthe nucleic acid hybridizes. The hybridization data obtained from thescan can be, for example, in the form of fluorescence intensities as afunction of location on the array.

Arrays can be formed on substrates fabricated with materials such aspaper; glass; plastic, for example, polypropylene, nylon, orpolystyrene; polyacrylamide; nitrocellulose; silicon; optical fiber; orany other suitable solid or semisolid support; and can be configured ina planar, for example, glass plates or silicon chips); or threedimensional, for example, pins, fibers, beads, particles, microtiterwells, and capillaries, configuration.

Methods for generating arrays are known in the art and can include forexample; photolithographic methods (U.S. Pat. Nos. 5,143,854, 5,510,270and 5,527,681); mechanical methods, for example, directed-flow methods(U.S. Pat. No. 5,384,261); pin-based methods (U.S. Pat. No. 5; 288;514); bead-based techniques (PCT US/93/04145); solid phaseoligonucleotide synthesis methods; or by other methods known to a personskilled in the art (see, e.g., Bier, F. F., et al., Adv Biochem EngBiotechnol 109:433-53 (2008); Hoheisel, J. D., Nat Rev Genet 7: 200-10(2006); Fan, J. B., et al., Methods Enzymol 410:57-73 (2006); Raqoussis,J. & Elvidge, G., Expert Rev Mol Design 6: 145-52 (2006); Mockler, T.C., et al., Genomics 85: 1-15 (2005), and references cited therein, theentire teachings of each of which are incorporated by reference herein).Many additional descriptions of the preparation and use ofoligonucleotide arrays for detection of polymorphisms can be found, forexample, in U.S. Pat. Nos. 6,858,394, 6,429,027, 5,445,934, 5,700,637,5,744,305, 5,945,334, 6,054,270, 6,300,063, 6,733,977, 7,364,858, EP 619321, and EP 373 203, the entire teachings of which are incorporated byreference herein. Methods for array production, hybridization, andanalysis are also described in Snijders et al., Nat. Genetics 29:263-264(2001); Klein et al., Proc. Natl. Acad. Sci. USA 96:4494-4499 (1999);Albertson et al., Breast Cancer Research and Treatment 78:289-298(2003); and Snijders et al., “BAC microarray based comparative genomichybridization,” in: Zhao et al., (eds), Bacterial ArtificialChromosomes: Methods and Protocols, Methods in Molecular Biology, HumanaPress (2002).

In some embodiments, oligonucleotide probes forming an array can beattached to a substrate by any number of techniques, including, but notlimited to, in situ synthesis, for example, high-density oligonucleotidearrays, using photolithographic techniques; spotting/printing a mediumto low density on glass, nylon, or nitrocellulose; by masking; and bydot-blotting on a nylon or nitrocellulose hybridization membrane. Insome embodiments, oligonucleotides can be immobilized via a linker,including but not limited to, by covalent, ionic, or physical linkage.Linkers for immobilizing nucleic acids and polypeptides, includingreversible or cleavable linkers, are known in the art (U.S. Pat. No.5,451,683 and WO98/20019). In some embodiments, oligonucleotides can benon-covalently immobilized on a substrate by hybridization to anchors,by means of magnetic beads, or in a fluid phase, for example, in wellsor capillaries.

An array can comprise oligonucleotide hybridization probes capable ofspecifically hybridizing to different genetic variations. In someembodiments, oligonucleotide arrays can comprise a plurality ofdifferent oligonucleotide probes coupled to a surface of a substrate indifferent known locations. In some embodiments, oligonucleotide probescan exhibit differential or selective binding to polymorphic sites, andcan be readily designed by one of ordinary skill in the art, forexample, an oligonucleotide that is perfectly complementary to asequence that encompasses a polymorphic site, for example, a sequencethat includes the polymorphic site, within it, or at one end, canhybridize preferentially to a nucleic acid comprising that sequence, asopposed to a nucleic acid comprising an alternate polymorphic variant.

In some embodiments, arrays can include multiple detection blocks, forexample, multiple groups of probes designed for detection of particularpolymorphisms. In some embodiments, these arrays can be used to analyzemultiple different polymorphisms. In some embodiments, detection blockscan be grouped within a single array or in multiple, separate arrays,wherein varying conditions, for example, conditions optimized forparticular polymorphisms, can be used during hybridization. Generaldescriptions of using oligonucleotide arrays for detection ofpolymorphisms can be found, for example, in U.S. Pat. Nos. 5,858,659 and5,837,832. In addition to oligonucleotide arrays, cDNA arrays can beused similarly in certain embodiments.

The methods described herein can include but are not limited toproviding an array as described herein; contacting the array with anucleic acid sample, and detecting binding of a nucleic acid from thenucleic acid sample to the array. In some embodiments, the method cancomprise amplifying nucleic acid from the nucleic acid sample, forexample, a region associated with PML or a region that includes anotherregion associated with PML. In some embodiments, the methods describedherein can include using an array that can identify differentialexpression patterns or copy numbers of one or more genes in nucleic acidsamples from control and affected individuals. For example, arrays ofprobes to a marker described herein can be used to identify geneticvariations between DNA from an affected subject, and control DNAobtained from an individual that does not have PML. Since thenucleotides on the array can contain sequence tags, their positions onthe array can be accurately known relative to the genomic sequence.

In some embodiments, it can be desirable to employ methods that candetect the presence of multiple genetic variations, for example,polymorphic variants at a plurality of polymorphic sites, in parallel orsubstantially simultaneously. In some embodiments, these methods cancomprise oligonucleotide arrays and other methods, including methods inwhich reactions, for example, amplification and hybridization, can beperformed in individual vessels, for example, within individual wells ofa multi-well plate or other vessel.

Determining the identity of a genetic variation can also include orconsist of reviewing a subject's medical history, where the medicalhistory includes information regarding the identity, copy number,presence or absence of one or more alleles or SNPs in the subject, e.g.,results of a genetic test.

In some embodiments extended runs of homozygosity (ROH) may be useful tomap recessive disease genes in outbred populations. Furthermore, even incomplex disorders, a high number of affected individuals may have thesame haplotype in the region surrounding a disease mutation. Therefore,a rare pathogenic variant and surrounding haplotype can be enriched infrequency in a group of affected individuals compared with the haplotypefrequency in a cohort of unaffected controls. Homozygous haplotypes (HH)that are shared by multiple affected individuals can be important forthe discovery of recessive disease genes in a condition such as PML. Insome embodiments, the traditional homozygosity mapping method can beextended by analyzing the haplotype within shared ROH regions toidentify homozygous segments of identical haplotype that are presentuniquely or at a higher frequency in PML probands compared to parentalcontrols. Such regions are termed risk homozygous haplotypes (rHH),which may contain low-frequency recessive variants that contribute toPML risk in a subset of PML patients.

Genetic variations can also be identified using any of a number ofmethods well known in the art. For example, genetic variations availablein public databases, which can be searched using methods and customalgorithms or algorithms known in the art, can be used. In someembodiments, a reference sequence can be from, for example, the humandraft genome sequence, publicly available in various databases, or asequence deposited in a database such as GenBank.

A comparison of one or more genomes relative to one or more othergenomes with array CGH, or a variety of other genetic variationdetection methods, can reveal the set of genetic variations between twogenomes, between one genome in comparison to multiple genomes, orbetween one set of genomes in comparison to another set of genomes. Insome embodiments, an array CGH experiment can be performed byhybridizing a single test genome against a pooled nucleic acid sample oftwo or more genomes, which can result in minimizing the detection ofhigher frequency variants in the experiment. In some embodiments, a testgenome can be hybridized alone (e.g., one-color detection) to amicroarray, for example, using array CGH or SNP genotyping methods, andthe comparison step to one or more reference genomes can be performed insilico to reveal the set of genetic variations in the test genomerelative to the one or more reference genomes. In one embodiment, asingle test genome is compared to a single reference genome in a 2-colorexperiment wherein both genomes are cohybridized to the microarray. Insome embodiments, the whole genome or whole exome from one or moresubjects is analyzed. In some embodiments, nucleic acid information hasalready been obtained for the whole genome or whole exome from one ormore individuals and the nucleic acid information is obtained from insilico analysis.

Any of the polynucleotides described, including polynucleotidescomprising a genetic variation, can be made synthetically using methodsknown in the art.

Methods of Detecting CNVs

Detection of genetic variations, specifically CNVs, can be accomplishedby one or more suitable techniques described herein. Generally,techniques that can selectively determine whether a particularchromosomal segment is present or absent in an individual can be usedfor genotyping CNVs. Identification of novel copy number variations canbe done by methods for assessing genomic copy number changes.

In some embodiments, methods include but are not limited to, methodsthat can quantitatively estimate the number of copies of a particulargenomic segment, but can also include methods that indicate whether aparticular segment is present in a nucleic acid sample or not. In someembodiments, the technique to be used can quantify the amount of segmentpresent, for example, determining whether a DNA segment is deleted,duplicated, or triplicated in subject, for example, Fluorescent In SituHybridization (FISH) techniques, and other methods described herein. Insome embodiments, methods include detection of copy number variationfrom array intensity and sequencing read depth using a stepwise Bayesianmodel (Zhang, et al., BMC Bioinformatics, 11:539 (2010)). In someembodiments, methods include detecting copy number variations usingshotgun sequencing, CNV-seq (Xie C., et al., BMC Bioinformatics, 10:80(2009)). In some embodiments, methods include analyzing next-generationsequencing (NGS) data for CNV detection using any one of severalalgorithms developed for each of the four broad methods for CNVdetection using NGS, namely the depth of coverage (DOC), read-pair (RP),split-read (SR) and assembly-based (AS) methods. (Teo et al.,Bioinformatics (2012)). In some embodiments, methods include combiningcoverage with map information for the identification of deletions andduplications in targeted sequence data (Nord et al., BMC Genomics,12:184 (2011)).

In some embodiments, other genotyping technologies can be used fordetection of CNVs, including but not limited to, karyotype analysis,Molecular Inversion Probe array technology, for example, Affymetrix SNPArray 6.0, and BeadArray Technologies, for example, Illumina GoldenGateand Infinium assays, as can other platforms such as NimbleGen HD2.1 orHD4.2, High-Definition Comparative Genomic Hybridization (CGH) arrays(Agilent Technologies), tiling array technology (Affymetrix), multiplexligation-dependent probe amplification (MLPA), Invader assay,fluorescence in situ hybridization, and, in one embodiment, ArrayComparative Genomic Hybridization (aCGH) methods. As described herein,karyotype analysis can be a method to determine the content andstructure of chromosomes in a nucleic acid sample. In some embodiments,karyotyping can be used, in lieu of aCGH, to detect translocations orinversions, which can be copy number neutral, and, therefore, notdetectable by aCGH. Information about amplitude of particular probes,which can be representative of particular alleles, can providequantitative dosage information for the particular allele, and byconsequence, dosage information about the CNV in question, since themarker can be selected as a marker representative of the CNV and can belocated within the CNV. In some embodiments, if the CNV is a deletion,the absence of particular marker allele is representative of thedeletion. In some embodiments, if the CNV is a duplication or a higherorder copy number variation, the signal intensity representative of theallele correlating with the CNV can represent the copy number. A summaryof methodologies commonly used is provided in Perkel (Perkel J. NatureMethods 5:447-453 (2008)).

PCR assays can be utilized to detect CNVs and can provide an alternativeto array analysis. In particular, PCR assays can enable detection ofprecise boundaries of gene/chromosome variants, at the molecular level,and which boundaries are identical in different individuals. PCR assayscan be based on the amplification of a junction fragment present only inindividuals that carry a deletion. This assay can convert the detectionof a loss by array CGH to one of a gain by PCR.

Examples of PCR techniques that can be used in the present disclosureinclude, but are not limited to quantitative PCR, real-time quantitativePCR (qPCR), quantitative fluorescent PCR (QF-PCR), multiplex fluorescentPCR (MF-PCR), real time PCR (RT-PCR), single cell PCR,PCR-RFLP/RT-PCR-RFLP, hot start PCR and Nested PCR. Other suitableamplification methods include the ligase chain reaction (LCR), ligationmediated PCR (LM-PCR), degenerate oligonucleotide probe PCR (DOP-PCR),transcription amplification, self-sustained sequence replication,selective amplification of target polynucleotide sequences, consensussequence primed polymerase chain reaction (CP-PCR), arbitrarily primedpolymerase chain reaction (AP-PCR) and nucleic acid sequence basedamplification (NASBA).

Alternative methods for the simultaneous interrogation of multipleregions include quantitative multiplex PCR of short fluorescentfragments (QMPSF), multiplex amplifiable probe hybridization (MAPH) andmultiplex ligation-dependent probe amplification (MLPA), in whichcopy-number differences for up to 40 regions can be scored in oneexperiment. Another approach can be to specifically target regions thatharbor known segmental duplications, which are often sites ofcopy-number variation. By targeting the variable nucleotides between twocopies of a segmental duplication (called paralogous sequence variants)using a SNP-genotyping method that provides independent fluorescenceintensities for the two alleles, it is possible to detect an increase inintensity of one allele compared with the other.

In some embodiments, the amplified piece of DNA can be bound to beadsusing the sequencing element of the nucleic acid tag under conditionsthat favor a single amplified piece of DNA molecule to bind a differentbead and amplification occurs on each bead. In some embodiments, suchamplification can occur by PCR. Each bead can be placed in a separatewell, which can be a picoliter-sized well. In some embodiments, eachbead is captured within a droplet of aPCR-reaction-mixture-in-oil-emulsion and PCR amplification occurs withineach droplet. The amplification on the bead results in each beadcarrying at least one million, at least 5 million, or at least 10million copies of the single amplified piece of DNA molecule.

In embodiments where PCR occurs in oil-emulsion mixtures, the emulsiondroplets are broken, the DNA is denatured and the beads carryingsingle-stranded nucleic acids clones are deposited into a well, such asa picoliter-sized well, for further analysis according to the methodsdescribed herein. These amplification methods allow for the analysis ofgenomic DNA regions. Methods for using bead amplification followed byfiber optics detection are described in Margulies et al., Nature, 15;437(7057):376-80 (2005), and as well as in US Publication ApplicationNos. 20020012930; 20030068629; 20030100102; 20030148344; 20040248161;20050079510, 20050124022; and 20060078909.

Another variation on the array-based approach can be to use thehybridization signal intensities that are obtained from theoligonucleotides employed on Affymetrix SNP arrays or in Illumina BeadArrays. Here hybridization intensities are compared with average valuesthat are derived from controls, such that deviations from these averagesindicate a change in copy number. As well as providing information aboutcopy number, SNP arrays have the added advantage of providing genotypeinformation. For example, they can reveal loss of heterozygosity, whichcould provide supporting evidence for the presence of a deletion, ormight indicate segmental uniparental disomy (which can recapitulate theeffects of structural variation in some genomic regions—Prader-Willi andAngelman syndromes, for example).

Many of the basic procedures followed in microarray-based genomeprofiling are similar, if not identical, to those followed in expressionprofiling and SNP analysis, including the use of specialized microarrayequipment and data-analysis tools. Since microarray-based expressionprofiling has been well established in the last decade, much can belearned from the technical advances made in this area. Examples of theuse of microarrays in nucleic acid analysis that can be used aredescribed in U.S. Pat. Nos. 6,300,063, 5,837,832, 6,969,589, 6,040,138,6,858,412, U.S. application Ser. No. 08/529,115, U.S. application Ser.No. 10/272,384, U.S. application Ser. No. 10/045,575, U.S. applicationSer. No. 10/264,571 and U.S. application Ser. No. 10/264,574. It shouldbe noted that there are also distinct differences such as target andprobe complexity, stability of DNA over RNA, the presence of repetitiveDNA and the need to identify single copy number alterations in genomeprofiling.

In some embodiments, the genetic variations detected comprise CNVs andcan be detected using array CGH. In some embodiments, array CGH can bebeen implemented using a wide variety of techniques. The initialapproaches used arrays produced from large-insert genomic clones such asbacterial artificial chromosomes (BACs). Producing sufficient BAC DNA ofadequate purity to make arrays is arduous, so several techniques toamplify small amounts of starting material have been employed. Thesetechniques include ligation-mediated PCR (Snijders et al., Nat. Genet.29:263-64), degenerate primer PCR using one or several sets of primers,and rolling circle amplification. BAC arrays that provide completegenome tiling paths are also available. Arrays made from less complexnucleic acids such as cDNAs, selected PCR products, and oligonucleotidescan also be used. Although most CGH procedures employ hybridization withtotal genomic DNA, it is possible to use reduced complexityrepresentations of the genome produced by PCR techniques. Computationalanalysis of the genome sequence can be used to design array elementscomplementary to the sequences contained in the representation. VariousSNP genotyping platforms, some of which use reduced complexity genomicrepresentations, can be useful for their ability to determine both DNAcopy number and allelic content across the genome. In some embodiments,small amounts of genomic DNA can be amplified with a variety of wholegenome or whole exome amplification methods prior to CGH analysis of thenucleic acid sample. A “whole exome,” as used herein, includes exonsthroughout the whole genome that are expressed in genes. Since exonselection has tissue and cell type specificity, these positions may bedifferent in the various cell types resulting from a splice variant oralternative splicing. A “whole genome,” as used herein, includes theentire genetic code of a genome.

The different basic approaches to array CGH provide different levels ofperformance, so some are more suitable for particular applications thanothers. The factors that determine performance include the magnitudes ofthe copy number changes, their genomic extents, the state andcomposition of the specimen, how much material is available foranalysis, and how the results of the analysis can be used. Manyapplications use reliable detection of copy number changes of much lessthan 50%, a more stringent requirement than for other microarraytechnologies. Note that technical details are extremely important anddifferent implementations of methods using the same array CGH approachcan yield different levels of performance. Various CGH methods are knownin the art and are equally applicable to one or more methods of thepresent disclosure. For example, CGH methods are disclosed in U.S. Pat.Nos. 7,030,231; 7,011,949; 7,014,997; 6,977,148; 6,951,761; and6,916,621, the disclosure from each of which is incorporated byreference herein in its entirety.

The data provided by array CGH are quantitative measures of DNA sequencedosage. Array CGH provides high-resolution estimates of copy numberaberrations, and can be performed efficiently on many nucleic acidsamples. The advent of array CGH technology makes it possible to monitorDNA copy number changes on a genomic scale and many projects have beenlaunched for studying the genome in specific diseases.

In some embodiments, whole genome array-based comparative genomehybridization (array CGH) analysis, or array CGH on a subset of genomicregions, can be used to efficiently interrogate human genomes forgenomic imbalances at multiple loci within a single assay. Thedevelopment of comparative genomic hybridization (CGH) (Kallioniemi etal., Science 258: 818-21 (1992)) provided the first efficient approachto scanning entire genomes for variations in DNA copy number. Theimportance of normal copy number variation involving large segments ofDNA has been unappreciated. Array CGH is a breakthrough technique inhuman genetics, which is attracting interest from clinicians working infields as diverse as cancer and IVF (In Vitro Fertilization). The use ofCGH microarrays in the clinic holds great promise for identifyingregions of genomic imbalance associated with disease. Advances fromidentifying chromosomal critical regions associated with specificphenotypes to identifying the specific dosage sensitive genes can leadto therapeutic opportunities of benefit to patients. Array CGH is aspecific, sensitive and rapid technique that can enable the screening ofthe whole genome in a single test. It can facilitate and accelerate thescreening process in human genetics and is expected to have a profoundimpact on the screening and counseling of patients with geneticdisorders. It is now possible to identify the exact location on thechromosome where an aberration has occurred and it is possible to mapthese changes directly onto the genomic sequence.

An array CGH approach provides a robust method for carrying out agenome-wide scan to find novel copy number variants (CNVs). The arrayCGH methods can use labeled fragments from a genome of interest, whichcan be competitively hybridized with a second differentially labeledgenome to arrays that are spotted with cloned DNA fragments, revealingcopy-number differences between the two genomes. Genomic clones (forexample, BACs), cDNAs, PCR products and oligonucleotides, can all beused as array targets. The use of array CGH with BACs was one of theearliest employed methods and is popular, owing to the extensivecoverage of the genome it provides, the availability of reliable mappingdata and ready access to clones. The last of these factors is importantboth for the array experiments themselves, and for confirmatory FISHexperiments.

In a typical CGH measurement, total genomic DNA is isolated from controland reference subjects, differentially labeled, and hybridized to arepresentation of the genome that allows the binding of sequences atdifferent genomic locations to be distinguished. More than two genomescan be compared simultaneously with suitable labels. Hybridization ofhighly repetitive sequences is typically suppressed by the inclusion ofunlabeled Cot-1 DNA in the reaction. In some embodiments of array CGH,it is beneficial to mechanically shear the genomic DNA in a nucleic acidsample, for example, with sonication, prior to its labeling andhybridization step. In another embodiment, array CGH may be performedwithout use of Cot-1 DNA or a sonication step in the preparation of thegenomic DNA in a nucleic acid sample. The relative hybridizationintensity of the test and reference signals at a given location can beproportional to the relative copy number of those sequences in the testand reference genomes. If the reference genome is normal then increasesand decreases in signal intensity ratios directly indicate DNA copynumber variation within the genome of the test cells. Data are typicallynormalized so that the modal ratio for the genome is set to somestandard value, typically 1.0 on a linear scale or 0.0 on a logarithmicscale. Additional measurements such as FISH or flow cytometry can beused to determine the actual copy number associated with a ratio level.

In some embodiments, an array CGH procedure can include the followingsteps. First, large-insert clones, for example, BACs can be obtainedfrom a supplier of clone libraries. Then, small amounts of clone DNA canbe amplified, for example, by degenerate oligonucleotide-primed (DOP)PCR or ligation-mediated PCR in order to obtain sufficient quantitiesneeded for spotting. Next, PCR products can be spotted onto glass slidesusing, for example, microarray robots equipped with high-precisionprinting pins. Depending on the number of clones to be spotted and thespace available on the microarray slide, clones can either be spottedonce per array or in replicate. Repeated spotting of the same clone onan array can increase precision of the measurements if the spotintensities are averaged, and allows for a detailed statistical analysisof the quality of the experiments. Subject and control DNAs can belabeled, for example, with either Cy3 or Cy5-dUTP using random primingand can be subsequently hybridized onto the microarray in a solutioncontaining an excess of Cot1-DNA to block repetitive sequences.Hybridizations can either be performed manually under a coverslip, in agasket with gentle rocking or, automatically using commerciallyavailable hybridization stations. These automated hybridization stationscan allow for an active hybridization process, thereby improving thereproducibility as well as reducing the actual hybridization time, whichincreases throughput. The hybridized DNAs can be detected through thetwo different fluorochromes using standard microarray scanning equipmentwith either a scanning confocal laser or a charge coupled device (CCD)camera-based reader, followed by spot identification using commerciallyor freely available software packages.

The use of CGH with arrays that comprise long oligonucleotides (60-100bp) can improve the detection resolution (in some embodiments, as smallas ˜3-5 kb sized CNVs on arrays designed for interrogation of humanwhole genomes) over that achieved using BACs (limited to 50-100 kb orlarger sized CNVs due to the large size of BAC clones). In someembodiments, the resolution of oligonucleotide CGH arrays is achievedvia in situ synthesis of 1-2 million unique features/probes permicroarray, which can include microarrays available from Roche NimbleGenand Agilent Technologies. In addition to array CGH methods for copynumber detection, other embodiments for partial or whole genome analysisof CNVs within a genome include, but are not limited to, use of SNPgenotyping microarrays and sequencing methods.

Another method for copy number detection that uses oligonucleotides canbe representational oligonucleotide microarray analysis (ROMA). It issimilar to that applied in the use of BAC and CGH arrays, but toincrease the signal-to-noise ratio, the ‘complexity’ of the input DNA isreduced by a method called representation or whole-genome sampling. Herethe DNA that is to be hybridized to the array can be treated byrestriction digestion and then ligated to adapters, which results in thePCR-based amplification of fragments in a specific size-range. As aresult, the amplified DNA can make up a fraction of the entire genomicsequence—that is, it is a representation of the input DNA that hassignificantly reduced complexity, which can lead to a reduction inbackground noise. Other suitable methods available to the skilled personcan also be used, and are within scope of the present disclosure.

A comparison of one or more genomes relative to one or more othergenomes with array CGH, or a variety of other CNV detection methods, canreveal the set of CNVs between two genomes, between one genome incomparison to multiple genomes, or between one set of genomes incomparison to another set of genomes. In some embodiments, an array CGHexperiment can be performed by hybridizing a single test genome againsta pooled nucleic acid sample of two or more genomes, which can result inminimizing the detection of higher frequency variants in the experiment.In some embodiments, a test genome can be hybridized alone (e.g.one-color detection) to a microarray, for example, using array CGH orSNP genotyping methods, and the comparison step to one or more referencegenomes can be performed in silico to reveal the set of CNVs in the testgenome relative to the one or more reference genomes. In one preferredembodiment, a single test genome is compared to a single referencegenome in a 2-color experiment wherein both genomes are cohybridized tothe microarray.

Array CGH can be used to identify genes that are causative or associatedwith a particular phenotype, condition, or disease by comparing the setof CNVs found in the affected cohort to the set of CNVs found in anunaffected cohort. An unaffected cohort may consist of any individualunaffected by the phenotype, condition, or disease of interest, but inone preferred embodiment is comprised of individuals or subjects thatare apparently healthy (normal). Methods employed for such analyses aredescribed in U.S. Pat. Nos. 7,702,468 and 7,957,913. In someembodiments, candidate genes that are causative or associated (e.g., abiomarker) with a phenotype, condition, or disease will be identified byCNVs that occur in the affected cohort but not in the unaffected cohort.In some embodiments, candidate genes that are causative or associated(e.g., a biomarker) with a phenotype, condition, or disease will beidentified by CNVs that occur at a statistically significant higherfrequency in the affected cohort as compared their frequency in theunaffected cohort. Thus, CNVs preferentially detected in the affectedcohort as compared to the unaffected cohort can serve as beacons ofgenes that are causative or associated with a particular phenotype,condition, or disease. Methods employed for such analyses are describedin U.S. Pat. No. 8,862,410. In some embodiments, CNV detection andcomparison methods can result in direct identification of the gene thatis causative or associated with phenotype, condition, or disease if theCNVs are found to overlap with or encompass the gene(s). In someembodiments, CNV detection and comparison methods can result inidentification of regulatory regions of the genome (e.g., promoters,enhancers, transcription factor binding sites) that regulate theexpression of one or more genes that are causative or associated withthe phenotype, condition, or disease of interest. In some embodiments,CNV detection and comparison methods can result in identification of aregion in the genome in linkage disequilibrium with a genetic variantthat is causative or associated with the phenotype, condition, ordisease of interest. In another embodiment, CNV detection and comparisonmethods can result in identification of a region in the genome inlinkage disequilibrium with a genetic variant that is protective againstthe condition or disease of interest.

Due to the large amount of genetic variation between any two genomes, ortwo sets (cohorts) of genomes, being compared, one preferred embodimentis to reduce the genetic variation search space by interrogating onlyCNVs, as opposed to the full set of genetic variants that can beidentified in an individual's genome or exome. The set of CNVs thatoccur only, or at a statistically higher frequency, in the affectedcohort as compared to the unaffected cohort can then be furtherinvestigated in targeted sequencing experiments to reveal the full setof genetic variants (of any size or type) that are causative orassociated (e.g., a biomarker) with a phenotype, condition, or disease.It can be appreciated to those skilled in the art that the targetedsequencing experiments are performed in both the affected and unaffectedcohorts in order to identify the genetic variants (e.g., SNVs andindels) that occur only, or at a statistically significant higherfrequency, in the affected individual or cohort as compared to theunaffected cohort. Methods employed for such analyses are described inU.S. Pat. No. 8,862,410.

A method of screening a subject for a disease or disorder can compriseassaying a nucleic acid sample from the subject to detect sequenceinformation for more than one genetic locus and comparing the sequenceinformation to a panel of nucleic acid biomarkers and screening thesubject for the presence or absence of the disease or disorder if one ormore of low frequency biomarkers in the panel are present in thesequence information.

The panel can comprise at least one nucleic acid biomarker (e.g.,genetic variation) for each of the more than one genetic loci. Forexample, the panel can comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,30, 35, 40, 45, 50, 75, 100, 150, 200 or more nucleic acid biomarkersfor each of the more than one genetic locus. In some embodiments, thepanel can comprise from about 2-1000 nucleic acid biomarkers. Forexample, the panel can comprise from about 2-900, 2-800, 2-700, 2-600,2-500, 2-400, 2-300, 2-200, 2-100, 25-900, 25-800, 25-700, 25-600,25-500, 25-400, 25-300, 25-200, 25-100, 100-1000, 100-900, 100-800,100-700, 100-600, 100-500, 100-400, 100-300, 100-200, 200-1000, 200-900,200-800, 200-700, 200-600, 200-500, 200-400, 200-300, 300-1000, 300-900,300-800, 300-700, 300-600, 300-500, 300-400, 400-1000, 400-900, 400-800,400-700, 400-600, 400-500, 500-1000, 500-900, 500-800, 500-700, 500-600,600-1000, 600-900, 600-800, 600-700, 700-1000, 700-900, 700-800,800-1000, 800-900, or 900-1000 nucleic acid biomarkers.

In some embodiments, a biomarker (e.g., genetic variation) can occur ata frequency of 1% or more in a population of subjects without thedisease or disorder. For example, a biomarker can occur at a frequencyof 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or more in a population ofsubjects without the disease or disorder. In some embodiments, abiomarker can occur at a frequency from about 1%-20% in a population ofsubjects without the disease or disorder. For example, a biomarker canoccur at a frequency of from about 1%-5% or 1%-10%, in a population ofsubjects without the disease or disorder.

The panel can comprise at least 2 low frequency biomarkers (e.g., lowfrequency genetic variations). For example, the panel can comprise atleast 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 3, 14, 15, 15, 17, 18, 19, 20,25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125,150, 175, 200, 250, 500, or 1000 or more low frequency biomarkers. Insome embodiments, the panel can comprise from about 2-1000 low frequencybiomarkers. For example, the panel can comprise from about 2-900, 2-800,2-700, 2-600, 2-500, 2-400, 2-300, 2-200, 2-100, 25-900, 25-800, 25-700,25-600, 25-500, 25-400, 25-300, 25-200, 25-100, 100-1000, 100-900,100-800, 100-700, 100-600, 100-500, 100-400, 100-300, 100-200, 200-1000,200-900, 200-800, 200-700, 200-600, 200-500, 200-400, 200-300, 300-1000,300-900, 300-800, 300-700, 300-600, 300-500, 300-400, 400-1000, 400-900,400-800, 400-700, 400-600, 400-500, 500-1000, 500-900, 500-800, 500-700,500-600, 600-1000, 600-900, 600-800, 600-700, 700-1000, 700-900,700-800, 800-1000, 800-900, or 900-1000 low frequency biomarkers.

In some embodiments, a low frequency biomarker can occur at a frequencyof 1% or less in a population of subjects without the disease ordisorder. For example, a low frequency biomarker can occur at afrequency of 0.5%, 0.1%, 0.05%, 0.01%, 0.005%, 0.001%, 0.0005%, or0.0001% or less in a population of subjects without the disease ordisorder. In some embodiments, a low frequency biomarker can occur at afrequency from about 0.0001%-0.1% in a population of subjects withoutthe disease or disorder. For example, a low frequency biomarker canoccur at a frequency of from about 0.0001%-0.0005%, 0.0001%-0.001%,0.0001%-0.005%, 0.0001%-0.01%, 0.0001%-0.05%, 0.0001%-0.1%,0.0001%-0.5%, 0.0005%-0.001%, 0.0005%-0.005%, 0.0005%-0.01%,0.0005%-0.05%, 0.0005%-0.1%, 0.0005%-0.5%, 0.0005%-1%, 0.001%-0.005%,0.001%-0.01%, 0.001%-0.05%, 0.001%-0.1%, 0.001%-0.5%, 0.001%-1%,0.005%-0.01%, 0.005%-0.05%, 0.005%-0.1%, 0.005%-0.5%, 0.005%-1%,0.01%-0.05%, 0.01%-0.1%, 0.01%-0.5%, 0.01%-1%, 0.05%-0.1%, 0.05%-0.5%,0.05%-1%, 0.1%-0.5%, 0.1%-1%, or 0.5%-1% in a population of subjectswithout the disease or disorder. In another embodiment, geneticbiomarker frequencies can range higher (e.g., 0.5% to 5%) and haveutility for diagnostic testing or drug development targeting the genesthat harbor such variants. Genetic variants of appreciable frequency andphenotypic effect in the general population are sometimes described asgoldilocks variants (e.g., see Cohen J Clin Lipidol. 2013 May-June; 7(3Suppl):S1-5 and Price et al. Am J Hum Genet. 2010 Jun. 11; 86(6):832-8).

In some embodiments, the presence or absence of the disease or disorderin the subject can be determined with at least 50% confidence. Forexample, the presence or absence of the disease or disorder in thesubject can be determined with at least 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 98%, 99%, or 100% confidence. In some embodiments,the presence or absence of the disease or disorder in the subject can bedetermined with a 50%-100% confidence. For example, the presence orabsence of the disease or disorder in the subject can be determined witha 60%-100%, 70%-100%, 80%-100%, 90%-100%, 50%-90%, 50%-80%, 50%-70%,50%-60%, 60%-90%, 60%-80%, 60%-70%, 70%-90%, 70%-80%, or 80%-90%. In oneembodiment, PML candidate CNVs and genes or regulatory loci associatedwith these CNVs can be determined or identified by comparing geneticdata from a cohort of normal individuals to that of an individual or acohort of individuals known to have, or be susceptible to PML.

In one embodiment, PML candidate CNV-subregions and genes associatedwith these regions can be determined or identified by comparing geneticdata from a cohort of normal individuals, such as a pre-existingdatabase of CNVs found in normal individuals termed the Normal VariationEngine (NVE), to that of a cohort of individual known to have, or besusceptible to PML.

In some embodiments, a nucleic acid sample from one individual ornucleic acid samples from a pool of 2 or more individuals without PMLcan serve as the reference nucleic acid sample(s) and the nucleic acidsample from an individual known to have PML or being tested to determineif they have PML can serve as the test nucleic acid sample. In onepreferred embodiment, the reference and test nucleic acid samples aresex-matched and co-hybridized on the CGH array. For example, referencenucleic acid samples can be labeled with a fluorophore such as Cy5,using methods described herein, and test subject nucleic acid samplescan be labeled with a different fluorophore, such as Cy3. Afterlabeling, nucleic acid samples can be combined and can be co-hybridizedto a microarray and analyzed using any of the methods described herein,such as aCGH. Arrays can then be scanned and the data can be analyzedwith software. Genetic alterations, such as CNVs, can be called usingany of the methods described herein. A list of the genetic alterations,such as CNVs, can be generated for one or more test subjects and/or forone or more reference subjects. Such lists of CNVs can be used togenerate a master list of non-redundant CNVs and/or CNV-subregions foreach type of cohort. In one embodiment, a cohort of test nucleic acidsamples, such as individuals known to have or suspected to have PML, canbe cohybridized with an identical sex-matched reference individual orsex-matched pool of reference individuals to generate a list ofredundant or non-redundant CNVs. Such lists can be based on the presenceor absence of one or more CNVs and/or CNV subregions present inindividuals within the cohort. In this manner, a master list can containa number of distinct CNVs and/or CNV-subregions, some of which areuniquely present in a single individual and some of which are present inmultiple individuals.

In some embodiments, CNVs and/or CNV-subregions of interest can beobtained by annotation of each CNV and/or CNV-subregion with relevantinformation, such as overlap with known genes and/or exons or intergenicregulatory regions such as transcription factor binding sites. In someembodiments, CNVs and/or CNV-subregions of interest can be obtained bycalculating the OR for a CNV and/or CNV-subregion according to thefollowing formula: OR=(PML/((# individuals in PML cohort)−PML))/(NVE/((#individuals in NVE cohort)−NVE)), where: PML=number of PML individualswith a CNV-subregion of interest and NVE=number of NVE subjects with theCNV-subregion of interest. If NVE=0, it can be set to 1 to avoid dealingwith infinities in cases where no CNVs are seen in the NVE. In someembodiments, a set of publicly available CNVs (e.g., the Database ofGenomic Variants) can be used as the Normal cohort for comparison to theaffected cohort CNVs. In another embodiment, the set of Normal cohortCNVs may comprise a private database generated by the same CNV detectionmethod, such as array CGH, or by a plurality of CNV detection methodsthat include, but are not limited to, array CGH, SNP genotyping arrays,custom CGH arrays, custom genotyping arrays, exome sequencing, wholegenome sequencing, targeted sequencing, FISH, q-PCR, or MLPA.

The number of individuals in any given cohort can be at least about 10,50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2500, 5000, 7500,10,000, 100,000, or more. In some embodiments, the number of individualsin any given cohort can be from 25-900, 25-800, 25-700, 25-600, 25-500,25-400, 25-300, 25-200, 25-100, 100-1000, 100-900, 100-800, 100-700,100-600, 100-500, 100-400, 100-300, 100-200, 200-1000, 200-900, 200-800,200-700, 200-600, 200-500, 200-400, 200-300, 300-1000, 300-900, 300-800,300-700, 300-600, 300-500, 300-400, 400-1000, 400-900, 400-800, 400-700,400-600, 400-500, 500-1000, 500-900, 500-800, 500-700, 500-600,600-1000, 600-900, 600-800, 600-700, 700-1000, 700-900, 700-800,800-1000, 800-900, or 900-1000.

In some embodiments, a method of determining relevance or statisticalsignificance of a genetic variant in a human subject to a disease or acondition associated with a genotype comprising screening a genome of ahuman subject with the disease or condition, such as by arrayComparative Genomic Hybridization, sequencing, or SNP genotyping, toprovide information on one or more genetic variants, such as those inTables 1 and 2. The method can further comprise comparing, such as via acomputer, information of said one or more genetic variants from thegenome of said subject to a compilation of data comprising frequenciesof genetic variants in at least 100 normal human subjects, such as thosewithout the disease or condition. The method can further comprisedetermining a statistical significance or relevance of said one or moregenetic variants from said comparison to the condition or disease ordetermining whether a genetic variant is present in said human subjectbut not present in said compilation of data from said comparison, or analgorithm can be used to call or identify significant geneticvariations, such as a genetic variation whose median log 2 ratio isabove or below a computed value. A computer can comprise computerexecutable logic that provides instructions for executing saidcomparison.

Different categories for CNVs of interest can be defined. In someembodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions occur within intergenic regions and are associatedwith an OR of at least 0.7. For example, CNVs/CNV-subregions can be ofinterest if the CNVs/CNV-subregions occur within intergenic regions andare associated with an OR of at least 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90,100, 110, 120, 130, 140, 150, 160, 170, 175, or more. In someembodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions occur within intergenic regions and are associatedwith an OR from about 0.7-200, 0.7-200, 0.7-90, 0.7-80, 0.7-70, 0.7-60,0.7-50, 0.7-40, 0.7-30, 0.7-20, 0.7-10, 0.7-5, 10-200, 10-180, 10-160,10-140, 10-120, 10-100, 10-80, 10-60, 10-40, 10-20, 20-200, 20-180,20-160, 20-140, 20-120, 20-100, 20-80, 20-60, 20-40, 30-200, 30-180,30-160, 30-140, 30-120, 30-100, 30-80, 30-60, 30-40, 40-200, 40-180,40-160, 40-140, 40-120, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50,50-200, 50-180, 50-160, 50-140, 50-120, 50-100, 50-90, 50-80, 50-70,50-60, 60-200, 60-180, 60-160, 60-140, 60-120, 60-100, 60-90, 60-80,60-70, 70-200, 70-180, 70-160, 70-140, 70-120, 70-100, 70-90, 70-80,80-200, 80-180, 80-160, 80-140, 80-120, 80-100, 80-90, 90-200, 90-180,90-160, 90-140, 90-120, or 90-100.

In some embodiments, CNVs/CNV-subregions can be of interest if theCNV/CNV-subregion overlaps a known gene, and is associated with an OR ofat least 1.8. For example, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions occur within intergenic regions and are associatedwith an OR of at least 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18,20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,150, 160, 170, 175, or more. In some embodiments, CNVs/CNV-subregionscan be of interest if the CNVs/CNV-subregions occur within exonicregions and are associated with an OR from about 1.8-200, 1.8-200,1.8-90, 1.8-80, 1.8-70, 1.8-60, 1.8-50, 1.8-40, 1.8-30, 1.8-20, 1.8-10,1.8-5, 10-200, 10-180, 10-160, 10-140, 10-120, 10-100, 10-80, 10-60,10-40, 10-20, 20-200, 20-180, 20-160, 20-140, 20-120, 20-100, 20-80,20-60, 20-40, 30-200, 30-180, 30-160, 30-140, 30-120, 30-100, 30-80,30-60, 30-40, 40-200, 40-180, 40-160, 40-140, 40-120, 40-100, 40-90,40-80, 40-70, 40-60, 40-50, 50-200, 50-180, 50-160, 50-140, 50-120,50-100, 50-90, 50-80, 50-70, 50-60, 60-200, 60-180, 60-160, 60-140,60-120, 60-100, 60-90, 60-80, 60-70, 70-200, 70-180, 70-160, 70-140,70-120, 70-100, 70-90, 70-80, 80-200, 80-180, 80-160, 80-140, 80-120,80-100, 80-90, 90-200, 90-180, 90-160, 90-140, 90-120, or 90-100.

In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 1 or more PML cases but only 0 Normal subjects. Insome embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 2 or more PML cases but only 0 or 1 Normalsubjects. In some embodiments, CNVs/CNV-subregions can be of interest ifthe CNVs/CNV-subregions are overlapping and/or non-overlapping, impactan exon, and they affect 1-5 PML cases but only 0 or 1 Normal subjects.For example, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 1 PML case but only 0 or 1 Normal subjects. Thiscan enable identification of rarer CNVs in cases with PML. In someembodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 1 PML case but only 0 or 1 Normal subjects, andare associated with an OR greater than 0.7, such as 1.8. In someembodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 2 PML cases but only 0 or 1 Normal subjects. Insome embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 3 PML cases but only 0 or 1 Normal subjects. Insome embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 4 PML cases but only 0 or 1 Normal subjects.

In some embodiments, CNVs/CNV-subregions can be of interest if the ORassociated with the sum of PML cases and the sum of NVE subjectsaffecting the same gene (including distinct CNVs/CNV-subregions) is atleast 0.67. For example, a CNV/CNV-subregion can be of interest if theOR associated with the sum of PML cases and the sum of NVE subjectsaffecting the same gene (including distinct CNVs/CNV-subregions) is atleast 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20,25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150,160, 170, 175, or more. In some embodiments, a CNVs/CNV-subregions canbe of interest if the OR associated with the sum of PML cases and thesum of NVE subjects affecting the same gene (including distinctCNVs/CNV-subregions) is from about 0.7-200, 0.7-200, 0.7-90, 0.7-80,0.7-70, 0.7-60, 0.7-50, 0.7-40, 0.7-30, 0.7-20, 0.7-10, 0.7-5, 10-200,10-180, 10-160, 10-140, 10-120, 10-100, 10-80, 10-60, 10-40, 10-20,20-200, 20-180, 20-160, 20-140, 20-120, 20-100, 20-80, 20-60, 20-40,30-200, 30-180, 30-160, 30-140, 30-120, 30-100, 30-80, 30-60, 30-40,40-200, 40-180, 40-160, 40-140, 40-120, 40-100, 40-90, 40-80, 40-70,40-60, 40-50, 50-200, 50-180, 50-160, 50-140, 50-120, 50-100, 50-90,50-80, 50-70, 50-60, 60-200, 60-180, 60-160, 60-140, 60-120, 60-100,60-90, 60-80, 60-70, 70-200, 70-180, 70-160, 70-140, 70-120, 70-100,70-90, 70-80, 80-200, 80-180, 80-160, 80-140, 80-120, 80-100, 80-90,90-200, 90-180, 90-160, 90-140, 90-120, or 90-100.

In some embodiments, CNVs/CNV-subregions can be of interest if the ORassociated with the sum of PML cases and the sum of NVE subjectsaffecting the same gene (including distinct CNVs/CNV-subregions) is atleast 1.8. For example, a CNV/CNV-subregion can be of interest if the ORassociated with the sum of PML cases and the sum of NVE subjectsaffecting the same gene (including distinct CNVs/CNV-subregions) is atleast 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35,40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 175,or more. In some embodiments, a CNVs/CNV-subregions can be of interestif the OR associated with the sum of PML cases and the sum of NVEsubjects affecting the same gene (including distinctCNVs/CNV-subregions) is from about 1.8-200, 1.8-200, 1.8-90, 1.8-80,1.8-70, 1.8-60, 1.8-50, 1.8-40, 1.8-30, 1.8-20, 1.8-10, 1.8-5, 10-200,10-180, 10-160, 10-140, 10-120, 10-100, 10-80, 10-60, 1040, 10-20,20-200, 20-180, 20-160, 20-140, 20-120, 20-100, 20-80, 20-60, 20-40,30-200, 30-180, 30-160, 30-140, 30-120, 30-100, 30-80, 30-60, 30-40,40-200, 40-180, 40-160, 40-140, 40-120, 40-100, 40-90, 40-80, 40-70,40-60, 40-50, 50-200, 50-180, 50-160, 50-140, 50-120, 50-100, 50-90,50-80, 50-70, 50-60, 60-200, 60-180, 60-160, 60-140, 60-120, 60-100,60-90, 60-80, 60-70, 70-200, 70-180, 70-160, 70-140, 70-120, 70-100,70-90, 70-80, 80-200, 80-180, 80-160, 80-140, 80-120, 80-100, 80-90,90-200, 90-180, 90-160, 90-140, 90-120, or 90-100.

In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions do not overlap (distinct CNV/CNV-subregion), butimpact the same gene (or regulatory locus) and are associated with an ORof at least 6 (Genic (distinct CNV-subregions); OR >6). For example,CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions do notoverlap, but impact the same gene (or regulatory locus), and areassociated with an OR of at 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35,40, 45, 50, or more. In some embodiments, CNVs/CNV-subregions can be ofinterest if the CNVs/CNV-subregions do not overlap, but impact the samegene (or regulatory locus), and are associated with an OR from about6-100, 6-50, 6-40, 6-30, 6-20, 6-10, 6-9, 6-8, 6-7, 8-100, 8-50, 8-40,8-30, 8-20, 8-10, 10-100, 10-50, 10-40, 10-30, 10-20, 20-100, 20-50,20-40, 20-30, 30-100, 30-50, 30-40, 40-100, 40-50, 50-100, or 5-7. TheCNV-subregion/gene can be an exonic or intronic part of the gene, orboth.

In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions do not overlap a known gene (e.g., are non-genic orintergenic) and they are associated with an OR of at least 7 (Exon+ve,PML >4, NVE <2). For example, CNVs/CNV-subregions can be of interest ifthe CNVs/CNV-subregion does not overlap a known gene (e.g., is non-genicor intergenic) and/or non-overlapping, impact an exon, affect 2 or morePML cases but only 0 or 1 Normal subjects and are associated with an ORof at least 8, 9, 10, 11, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, ormore. In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, affect 2 or more PML cases but only 0 or 1 Normal subjects and areassociated with an OR from about 7-100, 7-50, 7-40, 7-30, 7-20, 20-100,20-50, 20-40, 20-30, 30-100, 30-50, 30-40, 40-100, 40-50, 50-100, or7-11.

In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 1-5 PML cases but only 0 or 1 Normal subjects.This can enable identification of rarer CNVs in cases with PML. In someembodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 1 PML case but only 0 or 1 Normal subjects, andare associated with an OR greater than 1, such as 1.47, or from 1-2.5.In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 2 PML cases but only 0 or 1 Normal subjects andare associated with an OR greater than 2.5, such as 2.95, or from 2.5-4.In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 3 PML cases but only 0 or 1 Normal subjects andare associated with an OR greater than 4, such as 4.44, or from 4-5.5.In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions are overlapping and/or non-overlapping, impact anexon, and they affect 4 PML cases but only 0 or 1 Normal subjects andare associated with an OR greater than 5.5, such as 5.92, or from5.5-6.8.

In some embodiments, CNVs/CNV-subregions can be of interest if the ORassociated with the sum of PML cases and the sum of NVE subjectsaffecting the same gene (including distinct CNVs/CNV-subregions) is atleast 6. For example, a CNV/CNV-subregion can be of interest if the ORassociated with the sum of PML cases and the sum of NVE subjectsaffecting the same gene (including distinct CNVs/CNV-subregions) is atleast 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, or more.In some embodiments, a CNVs/CNV-subregions can be of interest if the ORassociated with the sum of PML cases and the sum of NVE subjectsaffecting the same gene (including distinct CNVs/CNV-subregions) is fromabout 6-100, 6-50, 6-40, 6-30, 6-20, 6-10, 6-9, 6-8, 6-7, 8-100, 8-50.8-40, 8-30, 8-20, 8-10, 10-100, 10-50, 10-40, 10-30, 10-20, 20-100,20-50, 20-40, 20-30, 30-100, 30-50, 30-40, 40-100, 40-50, 50-100, or5-7.

In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions impact an intron and they affect 5 or more PML casesbut only 0 or 1 Normal subjects and they are associated with an OR of atleast 7 (Intron+ve, PML >4, Normals <2). For example,CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions impactan intron and they affect 5 or more PML cases but only 0 or 1 Normalsubjects and they are associated with an OR of at least 8, 9, 10, 11,12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, or more. In someembodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions impact an intron and they affect 5 or more PML casesbut only 0 or 1 Normal subjects and they are associated with an OR fromabout 7-100, 7-50, 7-40, 7-30, 7-20, 20-100, 20-50, 20-40, 20-30,30-100, 30-50, 30-40, 40-100, 40-50, 50-100, or 7-11.CNVs/CNV-subregions impacting introns can be pathogenic (e.g., suchvariants can result in alternatively spliced mRNAs or loss of a microRNAbinding site, which may deleteriously impact the resulting protein'sstructure or expression level).

In some embodiments, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions occur within intergenic regions and are associatedwith an OR of greater than 30 (High OR intergenic (OR >30)). Forexample, CNVs/CNV-subregions can be of interest if theCNVs/CNV-subregions occur within intergenic regions and are associatedwith an OR of greater than 31, 32, 33, 34, 35, 40, 45, 50, 66, 60, 65,70, 75, 80, 85, 90, 95, 100 or more. In some embodiments,CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions impactoccur within intergenic regions and are associated with an OR from about30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-100, 40-90, 40-80,40-70, 40-60, 40-50, 50-100, 50-90, 50-80, 50-70, 50-60, 60-100, 60-90,60-80, 60-70, 70-100, 70-90, 70-80, 80-100, 80-90, or 90-100.

In some embodiments, a CNV/CNV-subregion can be of interest if theCNV/CNV-subregion overlaps a known gene, and is associated with an OR ofat least 10. In some embodiments, a CNV/CNV-subregion can be of interestif the CNV/CNV-subregion overlaps a known gene, is associated with an ORof at least 6, and if the OR associated with the sum of PML cases andthe sum of NVE subjects affecting the same gene (including distinctCNV-subregions) is at least 6.

Methods of Treatment

One embodiment of the present disclosure provides methods,pharmaceutical compositions, and kits for the treatment of a conditionin animal subjects. The condition can be HIV/AIDS, cancer, or anautoimmune disease. In some embodiments, the condition can be PML. Forexample, the condition can be multiple sclerosis. In some embodiments,the methods comprise administering one or more immunosuppressivemedications. In some embodiments, the pharmaceutical compositions andkits comprise one or more immunosuppressive medications. The one or moreimmunosuppressive medications can be adalimumab (e.g., HUMIRA),alemtuzumab (e.g., LEMTRADA), alemtuzumab (e.g., CAMPATH), azathioprine(e.g., IMURAN), belimumab (e.g., BENLYSTA), bevacizumab (e.g., AVASTIN),bortezomib (e.g., VELCADE), eculizumab (e.g., SOLIRIS), leflunomide,brentuximab vedotin (e.g., ADCETRIS), cetuximab (e.g., ERBITUX),cyclophosphamid, dimethyl fumarate (e.g., TECFIDERA), efalizumab (e.g.,RAPTIVA), fingolimod (e.g., GILENYA), fludarabine (e.g., FLUDARA),fumaric acid, imatinib (e.g., GLEEVEC, GLIVEC), infliximab (e.g.,REMICADE), methotrexate (e.g., TREXALL, RHEUMATREX), mycophenolatemofetil (e.g., CELLCEPT), natalizumab (e.g., TYSABRI), rituximab (e.g.,RITUXAN), daclizumab (e.g., ZINBRYTA), vedolizumab (ENTYVIO),ruxolitinib (e.g., JAKAFI, JAKAVI), ocrelizumab (e.g., OCREVUS), or anycombinations thereof. The term “animal subject” as used herein includeshumans as well as other mammals. The term “treating” as used hereinincludes achieving a therapeutic benefit and/or a prophylactic benefit.By therapeutic benefit is meant eradication or amelioration of theunderlying viral infection (e.g., HIV), cancer, or autoimmune disease.

In some embodiments, a subject can be currently treated with anantiretroviral medication. In some embodiments, a subject can bepreviously treated with an antiretroviral medication. In someembodiments, a subject can be not yet treated with an antiretroviralmedication. The antiretroviral medication can include but not limited toNucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-NucleosideReverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs),Fusion Inhibitors, Entry Inhibitors, Integrase Inhibitors,Pharmacokinetic Enhancers, and Combination HIV Medicines. In some cases,the Nucleoside Reverse Transcriptase Inhibitors can include but notlimited to abacavir, didanosine, emtricitabine, lamivudine, stavudine,tenofovir disoproxil fumarate, and zidovudine. In some cases, theNon-Nucleoside Reverse Transcriptase Inhibitors can include but notlimited to efavirenz, etravirine, nevirapine, and rilpivirine. In somecases, the Protease Inhibitors can include but not limited toatazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir,saquinavir, and tipranavir. In some cases, the Fusion Inhibitors caninclude but not limited to enfuvirtide. In some cases, the EntryInhibitors can include but not limited to maraviroc. In some cases, theIntegrase Inhibitors can include but not limited to dolutegravir,elvitegravir, and raltegravir. In some cases, the PharmacokineticEnhancers can include but not limited to cobicistat. In some cases, theCombination HIV Medicines can include but not limited to abacavir andlamivudine, abacavir, dolutegravir, and lamivudine, abacavir,lamivudine, and zidovudine, atazanavir and cobicistat, darunavir andcobicistat, efavirenz, emtricitabine, and tenofovir disoproxil fumarate,elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamidefumarate, elvitegravir, cobicistat, emtricitabine, and tenofovirdisoproxil fumarate, emtricitabine, rilpivirine, and tenofoviralafenamide, emtricitabine, rilpivirine, and tenofovir disoproxilfumarate, emtricitabine and tenofovir alafenamide, emtricitabine andtenofovir disoproxil fumarate, lamivudine and zidovudine, lopinavir andritonavir, and any combination of antiretroviral medications listedabove.

In some embodiments, such as when a subject is identified as having atleast one of the genetic variants described herein, an agent targetingthe JC Virus can be administered to the subject. In some embodiments, amedication can be administered to a subject that prevents PML fromdeveloping, or it can reduce, lessen, shorten and/or otherwiseameliorate the progression of PML, or symptoms that develop. Thepharmaceutical composition can modulate or target JC Virus. In someembodiments, a subject identified as having PML can be administered anagent that reduces a viral load in the subject. In some embodiments, animmunosuppressive agent can be administered prior to, or in conjunctionwith, an agent that reduces a viral load in the subject. In someembodiments, a subject identified as having a risk of developing PML canbe administered an agent that prevents an increase in a viral load inthe subject. In some embodiments, a subject identified as having a highrisk of developing PML can be administered an agent that prevents anincrease in a viral load in the subject. In some embodiments, animmunosuppressive agent can be administered prior to, or in conjunctionwith, an agent that prevents an increase in a viral load in the subject.The agent that reduces a viral load in the subject or that prevents anincrease in a viral load in the subject can be, for example, an agentthat targets JC Virus. Exemplary agents include antibodies, such asbroadly neutralizing JCV antibodies. For example, an agent can be abroadly neutralizing human monoclonal JC polyomavirus VP-1 specificantibody (See, e.g., Jelcic et al., Science Translational Medicine, Vol.7, Issue 306, pp. 306ra150 (2015) and Ray et al., Science TranslationalMedicine, Vol. 7, Issue 306, pp 306ra151 (2015)). Additional exemplaryagents include antiretroviral agents, cidofovir,hexadecyloxypropyl-cidofovir (a lipid-ester derivative), cytarabine(e.g., cytosine arabinoside), agents that block the 5HT2a receptor(e.g., olanzapine, zisprasidone, mirtazapine, cyproheptadine, andrisperidone), topoisomerase inhibitors (e.g., topotecan), andmefloquine.

In some embodiments, a pharmaceutical composition of the disclosure canbe administered to a subject at risk of developing PML, or to a subjectreporting one or more of the physiological symptoms of PML, even thougha screening of the condition cannot have been made. In some embodiments,a pharmaceutical composition of the disclosure can be administered to asubject not identified as having a risk of developing PML, or to asubject not identified as having one or more of the physiologicalsymptoms of PML, even though a screening of the condition cannot havebeen made.

The present disclosure also includes kits that can be used to treat acondition in animal subjects. These kits comprise one or moreimmunosuppressive medications and in some embodiments instructionsteaching the use of the kit according to the various methods andapproaches described herein. Such kits can also include information,such as scientific literature references, package insert materials,clinical trial results, and/or summaries of these and the like, whichindicate or establish the activities and/or advantages (or risks and/ordisadvantages) of the agent. Such information can be based on theresults of various studies, for example, studies using experimentalanimals involving in vivo models and studies based on human clinicaltrials. Kits described herein can be provided, marketed and/or promotedto health providers, including physicians, nurses, pharmacists,formulary officials, and the like.

In some aspects a host cell can be used for testing or administeringtherapeutics. In some embodiments, a host cell can comprise a nucleicacid comprising expression control sequences operably-linked to a codingregion. The host cell can be natural or non-natural. The non-naturalhost used in aspects of the method can be any cell capable of expressinga nucleic acid of the disclosure including, bacterial cells, fungalcells, insect cells, mammalian cells and plant cells. In some aspectsthe natural host is a mammalian tissue cell and the non-natural host isa different mammalian tissue cell. Other aspects of the method include anatural host that is a first cell normally residing in a first mammalianspecies and the non-natural host is a second cell normally residing in asecond mammalian species. In another alternative aspect, the method usesa first cell and the second cell that are from the same tissue type. Inthose aspects of the method where the coding region encodes a mammalianpolypeptide, the mammalian polypeptide may be a hormone. In otheraspects the coding region may encode a neuropeptide, an antibody, anantimetabolite, or a polypeptide or nucleotide therapeutic.

Expression control sequences can be those nucleotide sequences, both 5′and 3′ to a coding region, that are required for the transcription andtranslation of the coding region in a host organism. Regulatorysequences include a promoter, ribosome binding site, optional inducibleelements and sequence elements required for efficient 3′ processing,including polyadenylation. When the structural gene has been isolatedfrom genomic DNA, the regulatory sequences also include those intronicsequences required for splicing of the introns as part of mRNA formationin the target host.

Formulations, Routes of Administration, and Effective Doses

Yet another aspect of the present disclosure relates to formulations,routes of administration and effective doses for pharmaceuticalcompositions comprising an agent or combination of agents of the instantdisclosure. Such pharmaceutical compositions can be used to treat acondition (e.g., multiple sclerosis) as described above.

Compounds of the disclosure can be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, transdermal patch, pulmonary,vaginal, suppository, or parenteral (including intramuscular,intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneousand intravenous) administration or in a form suitable for administrationby aerosolization, inhalation or insufflation. General information ondrug delivery systems can be found in Ansel et al., PharmaceuticalDosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins,Baltimore Md. (1999).

In various embodiments, the pharmaceutical composition includes carriersand excipients (including but not limited to buffers, carbohydrates,mannitol, polypeptides, amino acids, antioxidants, bacteriostats,chelating agents, suspending agents, thickening agents and/orpreservatives), water, oils including those of petroleum, animal,vegetable or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil and the like, saline solutions, aqueous dextrose andglycerol solutions, flavoring agents, coloring agents, detackifiers andother acceptable additives, adjuvants, or binders, otherpharmaceutically acceptable auxiliary substances to approximatephysiological conditions, such as pH buffering agents, tonicityadjusting agents, emulsifying agents, wetting agents and the like.Examples of excipients include starch, glucose, lactose, sucrose,gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerolmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. In some embodiments, thepharmaceutical preparation is substantially free of preservatives. Inother embodiments, the pharmaceutical preparation can contain at leastone preservative. General methodology on pharmaceutical dosage forms isfound in Ansel et al., Pharmaceutical Dosage Forms and Drug DeliverySystems (Lippencott, Williams, & Wilkins, Baltimore Md. (1999)). It canbe recognized that, while any suitable carrier known to those ofordinary skill in the art can be employed to administer the compositionsof this disclosure, the type of carrier can vary depending on the modeof administration.

Compounds can also be encapsulated within liposomes using well-knowntechnology. Biodegradable microspheres can also be employed as carriersfor the pharmaceutical compositions of this disclosure. Suitablebiodegradable microspheres are disclosed, for example, in U.S. Pat. Nos.4,897,268, 5,075,109, 5,928,647, 5,811,128, 5,820,883, 5,853,763,5,814,344 and 5,942,252.

The compound can be administered in liposomes or microspheres (ormicroparticles). Methods for preparing liposomes and microspheres foradministration to a subject are well known to those of skill in the art.U.S. Pat. No. 4,789,734, the contents of which are hereby incorporatedby reference, describes methods for encapsulating biological materialsin liposomes. Essentially, the material is dissolved in an aqueoussolution, the appropriate phospholipids and lipids added, and along withsurfactants if required, and the material dialyzed or sonicated, asnecessary. A review of known methods is provided by G. Gregoriadis,Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp.2.sup.87-341 (Academic Press, 1979).

Microspheres formed of polymers or polypeptides are well known to thoseskilled in the art, and can be tailored for passage through thegastrointestinal tract directly into the blood stream. Alternatively,the compound can be incorporated and the microspheres, or composite ofmicrospheres, implanted for slow release over a period of time rangingfrom days to months. See, for example, U.S. Pat. Nos. 4,906,474,4,925,673 and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contentsof which are hereby incorporated by reference.

The concentration of drug can be adjusted, the pH of the solutionbuffered and the isotonicity adjusted to be compatible with intravenousinjection, as is well known in the art.

The compounds of the disclosure can be formulated as a sterile solutionor suspension, in suitable vehicles, well known in the art. Thepharmaceutical compositions can be sterilized by conventional,well-known sterilization techniques, or can be sterile filtered. Theresulting aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterilesolution prior to administration. Suitable formulations and additionalcarriers are described in Remington “The Science and Practice ofPharmacy” (20th Ed., Lippincott Williams & Wilkins, Baltimore Md.), theteachings of which are incorporated by reference in their entiretyherein.

The agents or their pharmaceutically acceptable salts can be providedalone or in combination with one or more other agents or with one ormore other forms. For example, a formulation can comprise one or moreagents in particular proportions, depending on the relative potencies ofeach agent and the intended indication. For example, in compositions fortargeting two different host targets, and where potencies are similar,about a 1:1 ratio of agents can be used. The two forms can be formulatedtogether, in the same dosage unit e.g., in one cream, suppository,tablet, capsule, aerosol spray, or packet of powder to be dissolved in abeverage; or each form can be formulated in a separate unit, e.g., twocreams, two suppositories, two tablets, two capsules, a tablet and aliquid for dissolving the tablet, two aerosol sprays, or a packet ofpowder and a liquid for dissolving the powder, etc.

The term “pharmaceutically acceptable salt” means those salts whichretain the biological effectiveness and properties of the agents used inthe present disclosure, and which are not biologically or otherwiseundesirable.

Typical salts are those of the inorganic ions, such as, for example,sodium, potassium, calcium, magnesium ions, and the like. Such saltsinclude salts with inorganic or organic acids, such as hydrochloricacid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,methanesulfonic acid, p toluenesulfonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, mandelic acid, malic acid, citric acid,tartaric acid or maleic acid. In addition, if the agent(s) contain acarboxyl group or other acidic group, it can be converted into apharmaceutically acceptable addition salt with inorganic or organicbases. Examples of suitable bases include sodium hydroxide, potassiumhydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine,diethanolamine, triethanolamine, and the like.

A pharmaceutically acceptable ester or amide refers to those whichretain biological effectiveness and properties of the agents used in thepresent disclosure, and which are not biologically or otherwiseundesirable. Typical esters include ethyl, methyl, isobutyl, ethyleneglycol, and the like. Typical amides include unsubstituted amides, alkylamides, dialkyl amides, and the like.

In some embodiments, an agent can be administered in combination withone or more other compounds, forms, and/or agents, e.g., as describedabove. Pharmaceutical compositions with one or more other active agentscan be formulated to comprise certain molar ratios. For example, molarratios of about 99:1 to about 1:99 of a first active agent to the otheractive agent can be used. In some subset of the embodiments, the rangeof molar ratios of a first active agent: other active agents areselected from about 80:20 to about 20:80; about 75:25 to about 25:75,about 70:30 to about 30:70, about 66:33 to about 33:66, about 60:40 toabout 40:60; about 50:50; and about 90:10 to about 10:90. The molarratio of a first active: other active agents can be about 1:9, and insome embodiments can be about 1:1. The two agents, forms and/orcompounds can be formulated together, in the same dosage unit e.g., inone cream, suppository, tablet, capsule, or packet of powder to bedissolved in a beverage; or each agent, form, and/or compound can beformulated in separate units, e.g., two creams, suppositories, tablets,two capsules, a tablet and a liquid for dissolving the tablet, anaerosol spray a packet of powder and a liquid for dissolving the powder,etc.

If necessary or desirable, the agents and/or combinations of agents canbe administered with still other agents. The choice of agents that canbe co-administered with the agents and/or combinations of agents of theinstant disclosure can depend, at least in part, on the condition beingtreated. Agents of particular use in the formulations of the presentdisclosure include, for example, any agent having a therapeutic effectfor a viral infection, including, e.g., drugs used to treat inflammatoryconditions. For example, in treatments for influenza, in someembodiments formulations of the instant disclosure can additionallycontain one or more conventional anti-inflammatory drugs, such as anNSAID, e.g., ibuprofen, naproxen, acetaminophen, ketoprofen, or aspirin.In some alternative embodiments for the treatment of influenzaformulations of the instant disclosure can additionally contain one ormore conventional influenza antiviral agents, such as amantadine,rimantadine, zanamivir, and oseltamivir. In treatments for retroviralinfections, such as HIV, formulations of the instant disclosure canadditionally contain one or more conventional antiviral drug, such asprotease inhibitors (lopinavir/ritonavir {e.g., KALETRA}, indinavir{e.g., CRIXIVAN}, ritonavir {e.g., NORVIR}, nelfinavir {e.g., VIRACEPT},saquinavir hard gel capsules {e.g., INVIRASE}, atazanavir {e.g.,REYATAZ}, amprenavir {e.g., AGENERASE}, fosamprenavir {e.g., TELZIR},tipranavir {e.g., APTIVUS}), reverse transcriptase inhibitors, includingnon-nucleoside and nucleoside/nucleotide inhibitors (AZT {zidovudine,e.g., Retrovir}, ddI {didanosine, e.g., VIDEX}, 3TC {lamivudine, e.g.,EPIVIR}, d4T {stavudine, e.g., ZERIT}, abacavir {e.g., ZIAGEN}, FTC{emtricitabine, e.g., EMTRIVA}, tenofovir {e.g., VIREAD}, efavirenz{e.g., SUSTIVA} and nevirapine {e.g., VIRAMUNE}), fusion inhibitors T20{enfuvirtide, e.g., FUZEON}, integrase inhibitors (Raltegravir, e.g.,ISENTRESS, MK-0518; and elvitegravir, e.g., VITEKTA, GS-9137), andmaturation inhibitors (bevirimat {PA-457}). As another example,formulations can additionally contain one or more supplements, such asvitamin C, E or other antioxidants.

The agent(s) (or pharmaceutically acceptable salts, esters or amidesthereof) can be administered per se or in the form of a pharmaceuticalcomposition wherein the active agent(s) is in an admixture or mixturewith one or more pharmaceutically acceptable carriers. A pharmaceuticalcomposition, as used herein, can be any composition prepared foradministration to a subject. Pharmaceutical compositions for use inaccordance with the present disclosure can be formulated in conventionalmanner using one or more physiologically acceptable carriers, comprisingexcipients, diluents, and/or auxiliaries, e.g., which facilitateprocessing of the active agents into preparations that can beadministered. Proper formulation can depend at least in part upon theroute of administration chosen. The agent(s) useful in the presentdisclosure, or pharmaceutically acceptable salts, esters, or amidesthereof, can be delivered to a subject using a number of routes or modesof administration, including oral, buccal, topical, rectal, transdermal,transmucosal, subcutaneous, intravenous, and intramuscular applications,as well as by inhalation.

For oral administration, the agents can be formulated readily bycombining the active agent(s) with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the agents of the disclosureto be formulated as tablets, including chewable tablets, pills, dragees,capsules, lozenges, hard candy, liquids, gels, syrups, slurries,powders, suspensions, elixirs, wafers, and the like, for oral ingestionby a subject to be treated. Such formulations can comprisepharmaceutically acceptable carriers including solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents. Asolid carrier can be one or more substances which can also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Generally, the agents of the disclosure can be included at concentrationlevels ranging from about 0.5%, about 5%, about 10%, about 20%, or about30% to about 50%, about 60%, about 70%, about 80% or about 90% by weightof the total composition of oral dosage forms, in an amount sufficientto provide a desired unit of dosage.

Aqueous suspensions for oral use can contain agent(s) of this disclosurewith pharmaceutically acceptable excipients, such as a suspending agent(e.g., methyl cellulose), a wetting agent (e.g., lecithin, lysolecithinand/or a long-chain fatty alcohol), as well as coloring agents,preservatives, flavoring agents, and the like.

In some embodiments, oils or non-aqueous solvents can be used to bringthe agents into solution, due to, for example, the presence of largelipophilic moieties. Alternatively, emulsions, suspensions, or otherpreparations, for example, liposomal preparations, can be used. Withrespect to liposomal preparations, any known methods for preparingliposomes for treatment of a condition can be used. See, for example,Bangham et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc.Natl Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein byreference. Ligands can also be attached to the liposomes to direct thesecompositions to particular sites of action. Agents of this disclosurecan also be integrated into foodstuffs, e.g., cream cheese, butter,salad dressing, or ice cream to facilitate solubilization,administration, and/or compliance in certain subject populations.

Pharmaceutical preparations for oral use can be obtained as a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; flavoring elements, cellulose preparations such as, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone(PVP). If desired, disintegrating agents can be added, such as the crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereofsuch as sodium alginate. The agents can also be formulated as asustained release preparation.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations that can be used orally include push fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active agents can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions canbe prepared in solutions, for example, in aqueous propylene glycolsolutions or can contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Suitable fillers or carriers with whichthe compositions can be administered include agar, alcohol, fats,lactose, starch, cellulose derivatives, polysaccharides,polyvinylpyrrolidone, silica, sterile saline and the like, or mixturesthereof used in suitable amounts. Solid form preparations includesolutions, suspensions, and emulsions, and can contain, in addition tothe active component, colorants, flavors, stabilizers, buffers,artificial and natural sweeteners, dispersants, thickeners, solubilizingagents, and the like.

A syrup or suspension can be made by adding the active compound to aconcentrated, aqueous solution of a sugar, e.g., sucrose, to which canalso be added any accessory ingredients. Such accessory ingredients caninclude flavoring, an agent to retard crystallization of the sugar or anagent to increase the solubility of any other ingredient, e.g., as apolyhydric alcohol, for example, glycerol or sorbitol.

When formulating compounds of the disclosure for oral administration, itcan be desirable to utilize gastroretentive formulations to enhanceabsorption from the gastrointestinal (GI) tract. A formulation which isretained in the stomach for several hours can release compounds of thedisclosure slowly and provide a sustained release that can be preferredin some embodiments of the disclosure. Disclosure of suchgastro-retentive formulations are found in Klausner E. A., et al.,Pharm. Res. 20, 1466-73 (2003); Hoffman, A. et al., Int. J. Pharm. 11,141-53 (2004), Streubel, A., et al. Expert Opin. Drug Deliver. 3, 217-3,and Chavanpatil, M. D. et al., Int. J. Pharm. (2006). Expandable,floating and bioadhesive techniques can be utilized to maximizeabsorption of the compounds of the disclosure.

The compounds of the disclosure can be formulated for parenteraladministration (e.g., by injection, for example, bolus injection orcontinuous infusion) and can be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions can take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample, solutions in aqueous polyethylene glycol.

For injectable formulations, the vehicle can be chosen from those knownin art to be suitable, including aqueous solutions or oil suspensions,or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil,as well as elixirs, mannitol, dextrose, or a sterile aqueous solution,and similar pharmaceutical vehicles. The formulation can also comprisepolymer compositions which are biocompatible, biodegradable, such aspoly(lactic-co-glycolic)acid. These materials can be made into micro ornanospheres, loaded with drug and further coated or derivatized toprovide superior sustained release performance. Vehicles suitable forperiocular or intraocular injection include, for example, suspensions oftherapeutic agent in injection grade water, liposomes and vehiclessuitable for lipophilic substances. Other vehicles for periocular orintraocular injection are well known in the art.

In some embodiments, the composition is formulated in accordance withroutine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition can also include a solubilizingagent and a local anesthetic such as lidocaine to ease pain at the siteof the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. Where the composition is to be administered by infusion,it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

When administration is by injection, the active compound can beformulated in aqueous solutions, specifically in physiologicallycompatible buffers such as Hanks solution, Ringer's solution, orphysiological saline buffer. The solution can contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Alternatively,the active compound can be in powder form for constitution with asuitable vehicle, e.g., sterile pyrogen-free water, before use. In someembodiments, the pharmaceutical composition does not comprise anadjuvant or any other substance added to enhance the immune responsestimulated by the peptide. In some embodiments, the pharmaceuticalcomposition comprises a substance that inhibits an immune response tothe peptide. Methods of formulation are known in the art, for example,as disclosed in Remington's Pharmaceutical Sciences, latest edition,Mack Publishing Co., Easton P.

In addition to the formulations described previously, the agents canalso be formulated as a depot preparation. Such long acting formulationscan be administered by implantation or transcutaneous delivery (forexample, subcutaneously or intramuscularly), intramuscular injection oruse of a transdermal patch. Thus, for example, the agents can beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

In some embodiments, pharmaceutical compositions comprising one or moreagents of the present disclosure exert local and regional effects whenadministered topically or injected at or near particular sites ofinfection. Direct topical application, e.g., of a viscous liquid,solution, suspension, dimethylsulfoxide (DMSO)-based solutions,liposomal formulations, gel, jelly, cream, lotion, ointment,suppository, foam, or aerosol spray, can be used for localadministration, to produce for example, local and/or regional effects.Pharmaceutically appropriate vehicles for such formulation include, forexample, lower aliphatic alcohols, polyglycols (e.g., glycerol orpolyethylene glycol), esters of fatty acids, oils, fats, silicones, andthe like. Such preparations can also include preservatives (e.g.,p-hydroxybenzoic acid esters) and/or antioxidants (e.g., ascorbic acidand tocopherol). See also Dermatological Formulations: Percutaneousabsorption, Barry (Ed.), Marcel Dekker Incl, 1983.

Pharmaceutical compositions of the present disclosure can contain acosmetically or dermatologically acceptable carrier. Such carriers arecompatible with skin, nails, mucous membranes, tissues and/or hair, andcan include any conventionally used cosmetic or dermatological carriermeeting these requirements. Such carriers can be readily selected by oneof ordinary skill in the art. In formulating skin ointments, an agent orcombination of agents of the instant disclosure can be formulated in anoleaginous hydrocarbon base, an anhydrous absorption base, awater-in-oil absorption base, an oil-in-water water-removable baseand/or a water-soluble base. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Ointments and creams can, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions can be formulated with an aqueous or oily base and canin general also containing one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the disclosure include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

The compositions according to the present disclosure can be in any formsuitable for topical application, including aqueous, aqueous-alcoholicor oily solutions, lotion or serum dispersions, aqueous, anhydrous oroily gels, emulsions obtained by dispersion of a fatty phase in anaqueous phase (0/W or oil in water) or, conversely, (W/O or water inoil), microemulsions or alternatively microcapsules, microparticles orlipid vesicle dispersions of ionic and/or nonionic type. Thesecompositions can be prepared according to conventional methods. Otherthan the agents of the disclosure, the amounts of the variousconstituents of the compositions according to the disclosure are thoseconventionally used in the art. These compositions in particularconstitute protection, treatment or care creams, milks, lotions, gels orfoams for the face, for the hands, for the body and/or for the mucousmembranes, or for cleansing the skin. The compositions can also consistof solid preparations constituting soaps or cleansing bars.

Compositions of the present disclosure can also contain adjuvants commonto the cosmetic and dermatological fields, such as hydrophilic orlipophilic gelling agents, hydrophilic or lipophilic active agents,preserving agents, antioxidants, solvents, fragrances, fillers,sunscreens, odor-absorbers and dyestuffs. The amounts of these variousadjuvants are those conventionally used in the fields considered and,for example, are from about 0.01% to about 20% of the total weight ofthe composition. Depending on their nature, these adjuvants can beintroduced into the fatty phase, into the aqueous phase and/or into thelipid vesicles.

In some embodiments, ocular viral infections can be effectively treatedwith ophthalmic solutions, suspensions, ointments or inserts comprisingan agent or combination of agents of the present disclosure. Eye dropscan be prepared by dissolving the active ingredient in a sterile aqueoussolution such as physiological saline, buffering solution, etc., or bycombining powder compositions to be dissolved before use. Other vehiclescan be chosen, as is known in the art, including but not limited to:balance salt solution, saline solution, water soluble polyethers such aspolyethylene glycol, polyvinyls, such as polyvinyl alcohol and povidone,cellulose derivatives such as methylcellulose and hydroxypropylmethylcellulose, petroleum derivatives such as mineral oil and whitepetrolatum, animal fats such as lanolin, polymers of acrylic acid suchas carboxypolymethylene gel, vegetable fats such as peanut oil andpolysaccharides such as dextrans, and glycosaminoglycans such as sodiumhyaluronate. If desired, additives ordinarily used in the eye drops canbe added. Such additives include isotonizing agents (e.g., sodiumchloride, etc.), buffer agent (e.g., boric acid, sodium monohydrogenphosphate, sodium dihydrogen phosphate, etc.), preservatives (e.g.,benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.),thickeners (e.g., saccharide such as lactose, mannitol, maltose, etc.;e.g., hyaluronic acid or its salt such as sodium hyaluronate, potassiumhyaluronate, etc.; e.g., mucopolysaccharide such as chondroitin sulfate,etc.; e.g., sodium polyacrylate, carboxyvinyl polymer, crosslinkedpolyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose,carboxymethyl cellulose, hydroxy propyl cellulose or other agents knownto those skilled in the art).

The solubility of the components of the present compositions can beenhanced by a surfactant or other appropriate co-solvent in thecomposition. Such cosolvents include polysorbate 20, 60, and 80,Pluronic F68, F-84 and P-103, cyclodextrin, or other agents known tothose skilled in the art. Such cosolvents can be employed at a level offrom about 0.01% to 2% by weight.

The compositions of the disclosure can be packaged in multidose form.Preservatives can be preferred to prevent microbial contamination duringuse. Suitable preservatives include: benzalkonium chloride, thimerosal,chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol,edetate disodium, sorbic acid, Onamer M, or other agents known to thoseskilled in the art. In the prior art ophthalmic products, suchpreservatives can be employed at a level of from 0.004% to 0.02%. In thecompositions of the present application the preservative, preferablybenzalkonium chloride, can be employed at a level of from 0.001% to lessthan 0.01%, e.g., from 0.001% to 0.008%, preferably about 0.005% byweight. It has been found that a concentration of benzalkonium chlorideof 0.005% can be sufficient to preserve the compositions of the presentdisclosure from microbial attack.

In some embodiments, the agents of the present disclosure are deliveredin soluble rather than suspension form, which allows for more rapid andquantitative absorption to the sites of action. In general, formulationssuch as jellies, creams, lotions, suppositories and ointments canprovide an area with more extended exposure to the agents of the presentdisclosure, while formulations in solution, e.g., sprays, provide moreimmediate, short-term exposure.

In some embodiments relating to topical/local application, thepharmaceutical compositions can include one or more penetrationenhancers. For example, the formulations can comprise suitable solid orgel phase carriers or excipients that increase penetration or helpdelivery of agents or combinations of agents of the disclosure across apermeability barrier, e.g., the skin. Many of thesepenetration-enhancing compounds are known in the art of topicalformulation, and include, e.g., water, alcohols (e.g., terpenes likemethanol, ethanol, 2-propanol), sulfoxides (e.g., dimethyl sulfoxide,decylmethyl sulfoxide, tetradecylmethyl sulfoxide), pyrrolidones (e.g.,2-pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone),laurocapram, acetone, dimethylacetamide, dimethylformamide,tetrahydrofurfuryl alcohol, L-α-amino acids, anionic, cationic,amphoteric or nonionic surfactants (e.g., isopropyl myristate and sodiumlauryl sulfate), fatty acids, fatty alcohols (e.g., oleic acid), amines,amides, clofibric acid amides, hexamethylene lauramide, proteolyticenzymes, α-bisabolol, d-limonene, urea and N,N-diethyl-m-toluamide, andthe like. Additional examples include humectants (e.g., urea), glycols(e.g., propylene glycol and polyethylene glycol), glycerol monolaurate,alkanes, alkanols, ORGELASE, calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and/or otherpolymers. In some embodiments, the pharmaceutical compositions caninclude one or more such penetration enhancers.

In some embodiments, the pharmaceutical compositions for local/topicalapplication can include one or more antimicrobial preservatives such asquaternary ammonium compounds, organic mercurials, p-hydroxy benzoates,aromatic alcohols, chlorobutanol, and the like.

In some embodiments, the pharmaceutical compositions can be orally- orrectally delivered solutions, suspensions, ointments, enemas and/orsuppositories comprising an agent or combination of agents of thepresent disclosure.

In some embodiments, the pharmaceutical compositions can be aerosolsolutions, suspensions or dry powders comprising an agent or combinationof agents of the present disclosure. The aerosol can be administeredthrough the respiratory system or nasal passages. For example, oneskilled in the art can recognize that a composition of the presentdisclosure can be suspended or dissolved in an appropriate carrier,e.g., a pharmaceutically acceptable propellant, and administereddirectly into the lungs using a nasal spray or inhalant. For example, anaerosol formulation comprising an agent can be dissolved, suspended oremulsified in a propellant or a mixture of solvent and propellant, e.g.,for administration as a nasal spray or inhalant. Aerosol formulationscan contain any acceptable propellant under pressure, such as acosmetically or dermatologically or pharmaceutically acceptablepropellant, as conventionally used in the art.

An aerosol formulation for nasal administration is generally an aqueoussolution designed to be administered to the nasal passages in drops orsprays. Nasal solutions can be similar to nasal secretions in that theyare generally isotonic and slightly buffered to maintain a pH of about5.5 to about 6.5, although pH values outside of this range canadditionally be used. Antimicrobial agents or preservatives can also beincluded in the formulation.

An aerosol formulation for inhalations and inhalants can be designed sothat the agent or combination of agents of the present disclosure iscarried into the respiratory tree of the subject when administered bythe nasal or oral respiratory route. Inhalation solutions can beadministered, for example, by a nebulizer. Inhalations or insufflations,comprising finely powdered or liquid drugs, can be delivered to therespiratory system as a pharmaceutical aerosol of a solution orsuspension of the agent or combination of agents in a propellant, e.g.,to aid in disbursement. Propellants can be liquefied gases, includinghalocarbons, for example, fluorocarbons such as fluorinated chlorinatedhydrocarbons, hydrochlorofluorocarbons, and hydrochlorocarbons, as wellas hydrocarbons and hydrocarbon ethers.

Halocarbon propellants useful in the present disclosure includefluorocarbon propellants in which all hydrogens are replaced withfluorine, chlorofluorocarbon propellants in which all hydrogens arereplaced with chlorine and at least one fluorine, hydrogen-containingfluorocarbon propellants, and hydrogen-containing chlorofluorocarbonpropellants. Halocarbon propellants are described in Johnson, U.S. Pat.No. 5,376,359; Byron et al., U.S. Pat. No. 5,190,029; and Purewal etal., U.S. Pat. No. 5,776,434. Hydrocarbon propellants useful in thedisclosure include, for example, propane, isobutane, n-butane, pentane,isopentane and neopentane. A blend of hydrocarbons can also be used as apropellant. Ether propellants include, for example, dimethyl ether aswell as the ethers. An aerosol formulation of the disclosure can alsocomprise more than one propellant. For example, the aerosol formulationcan comprise more than one propellant from the same class, such as twoor more fluorocarbons; or more than one, more than two, more than threepropellants from different classes, such as a fluorohydrocarbon and ahydrocarbon. Pharmaceutical compositions of the present disclosure canalso be dispensed with a compressed gas, e.g., an inert gas such ascarbon dioxide, nitrous oxide or nitrogen.

Aerosol formulations can also include other components, for example,ethanol, isopropanol, propylene glycol, as well as surfactants or othercomponents such as oils and detergents. These components can serve tostabilize the formulation and/or lubricate valve components.

The aerosol formulation can be packaged under pressure and can beformulated as an aerosol using solutions, suspensions, emulsions,powders and semisolid preparations. For example, a solution aerosolformulation can comprise a solution of an agent of the disclosure in(substantially) pure propellant or as a mixture of propellant andsolvent. The solvent can be used to dissolve the agent and/or retard theevaporation of the propellant. Solvents useful in the disclosureinclude, for example, water, ethanol and glycols. Any combination ofsuitable solvents can be use, optionally combined with preservatives,antioxidants, and/or other aerosol components.

An aerosol formulation can also be a dispersion or suspension. Asuspension aerosol formulation can comprise a suspension of an agent orcombination of agents of the instant disclosure. Dispersing agentsuseful in the disclosure include, for example, sorbitan trioleate, oleylalcohol, oleic acid, lecithin and corn oil. A suspension aerosolformulation can also include lubricants, preservatives, antioxidant,and/or other aerosol components.

An aerosol formulation can similarly be formulated as an emulsion. Anemulsion aerosol formulation can include, for example, an alcohol suchas ethanol, a surfactant, water and a propellant, as well as an agent orcombination of agents of the disclosure. The surfactant used can benonionic, anionic or cationic. One example of an emulsion aerosolformulation comprises, for example, ethanol, surfactant, water andpropellant. Another example of an emulsion aerosol formulationcomprises, for example, vegetable oil, glyceryl monostearate andpropane.

The compounds of the disclosure can be formulated for administration assuppositories. A low melting wax, such as a mixture of triglycerides,fatty acid glycerides, Witepsol S55 (trademark of Dynamite NobelChemical, Germany), or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the disclosure can be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

It is envisioned additionally, that the compounds of the disclosure canbe attached releasably to biocompatible polymers for use in sustainedrelease formulations on, in or attached to inserts for topical,intraocular, periocular, or systemic administration. The controlledrelease from a biocompatible polymer can be utilized with a watersoluble polymer to form an instillable formulation, as well. Thecontrolled release from a biocompatible polymer, such as for example,PLGA microspheres or nanospheres, can be utilized in a formulationsuitable for intra ocular implantation or injection for sustainedrelease administration, as well any suitable biodegradable andbiocompatible polymer can be used.

In one aspect of the disclosure, the subject's carrier status of any ofthe genetic variation risk variants described herein, or geneticvariants identified via other analysis methods within the genes orregulatory loci that are identified by the CNVs or SNVs describedherein, can be used to help determine whether a particular treatmentmodality, such as any one of the above, or a combination thereof, shouldbe administered. Whether a treatment option such as any of the abovementioned treatment options is administered can be determined based onthe presence or absence of a particular genetic variation risk variantin the individual, or by monitoring expression of genes that areassociated with the variants of the present disclosure. Expressionlevels and/or mRNA levels can thus be determined before and duringtreatment to monitor its effectiveness. Alternatively, or concomitantly,the status with respect to a genetic variation, and or genotype and/orhaplotype status of at least one risk variant for PML presented hereincan be determined before and during treatment to monitor itseffectiveness. It can also be appreciated by those skilled in the artthat aberrant expression levels of a gene impacted by a CNV or othermutations found as a consequence of targeted sequencing of theCNV-identified gene can be assayed or diagnostically tested for bymeasuring the polypeptide expression level of said aberrantly expressedgene. In another embodiment, aberrant expression levels of a gene mayresult from a CNV impacting a DNA sequence (e.g., transcription factorbinding site) that regulates a gene whose aberrant expression level isinvolved in or causes PML, or other mutations found as a consequence oftargeted sequencing of the CNV-identified gene regulatory sequence, canbe assayed or diagnostically tested for by measuring the polypeptideexpression level of the gene involved in or causative of PML. In someembodiments, a specific CNV mutation within a gene, or other specificmutations found upon targeted sequencing of a CNV-identified gene foundto be involved in or causative of PML, may cause an aberrant structuralchange in the expressed polypeptide that results from said genemutations and the altered polypeptide structure(s) can be assayed viavarious methods know to those skilled in the art.

Alternatively, biological networks or metabolic pathways related to thegenes within, or associated with, the genetic variations describedherein can be monitored by determining mRNA and/or polypeptide levels.This can be done for example, by monitoring expression levels ofpolypeptides for several genes belonging to the network and/or pathwayin nucleic acid samples taken before and during treatment.Alternatively, metabolites belonging to the biological network ormetabolic pathway can be determined before and during treatment.Effectiveness of the treatment is determined by comparing observedchanges in expression levels/metabolite levels during treatment tocorresponding data from healthy subjects.

In some embodiments, the genetic variations described herein and/orthose subsequently found (e.g., via other genetic analysis methods suchas sequencing) via targeted analysis of those genes initially identifiedby the genetic variations described herein, can be used to preventadverse effects associated with a therapeutic agent, such as duringclinical trials. For example, individuals who are carriers of at leastone at-risk genetic variation can be more likely to respond negativelyto a therapeutic agent, such as an immunosuppressive agent. For example,carriers of certain genetic variants may be more likely to show anadverse response to the therapeutic agent. In some embodiments, one ormore of the genetic variations employed during clinical trials for agiven therapeutic agent can be used in a companion diagnostic test thatis administered to the patient prior to administration of thetherapeutic agent to determine if the patient is likely to have afavorable or an adverse response to the therapeutic agent.

The genetic variations described herein can be used for determiningwhether a subject is administered a pharmaceutical agent, such as animmunosuppressive drug. Certain combinations of variants, includingthose described herein, but also combinations with other risk variantsfor PML, can be suitable for one selection of treatment options, whileother variant combinations can be suitable for selection of othertreatment options. Such combinations of variants can include onevariant, two variants, three variants, or four or more variants, asneeded to determine with clinically reliable accuracy the selection oftreatment module. In another embodiment, information from testing forthe genetic variations described herein, or other rare geneticvariations in or near the genes described herein, may be combined withinformation from other types of testing (e.g., a JCV antibody test,CD62L test, or CSF IgM oligoclonal bands test) for selection oftreatment options.

Kits

Kits useful in the methods of the disclosure comprise components usefulin any of the methods described herein, including for example, primersfor nucleic acid amplification, hybridization probes for detectinggenetic variation, or other marker detection, restriction enzymes,nucleic acid probes, optionally labeled with suitable labels,allele-specific oligonucleotides, antibodies that bind to an alteredpolypeptide encoded by a nucleic acid of the disclosure as describedherein or to a wild type polypeptide encoded by a nucleic acid of thedisclosure as described herein, means for amplification of geneticvariations or fragments thereof, means for analyzing the nucleic acidsequence of nucleic acids comprising genetic variations as describedherein, means for analyzing the amino acid sequence of a polypeptideencoded by a genetic variation, or a nucleic acid associated with agenetic variation, etc. The kits can for example, include necessarybuffers, nucleic acid primers for amplifying nucleic acids, and reagentsfor allele-specific detection of the fragments amplified using suchprimers and necessary enzymes (e.g., DNA polymerase). Additionally, kitscan provide reagents for assays to be used in combination with themethods of the present disclosure, for example, reagents for use withother screening assays for PML.

In some embodiments, the disclosure pertains to a kit for assaying anucleic acid sample from a subject to detect the presence of a geneticvariation, wherein the kit comprises reagents necessary for selectivelydetecting at least one particular genetic variation in the genome of theindividual. In some embodiments, the disclosure pertains to a kit forassaying a nucleic acid sample from a subject to detect the presence ofat least one particular allele of at least one polymorphism associatedwith a genetic variation in the genome of the subject. In someembodiments, the reagents comprise at least one contiguousoligonucleotide that hybridizes to a fragment of the genome of theindividual comprising at least genetic variation. In some embodiments,the reagents comprise at least one pair of oligonucleotides thathybridize to opposite strands of a genomic segment obtained from asubject, wherein each oligonucleotide primer pair is designed toselectively amplify a fragment of the genome of the individual thatincludes at least one genetic variation, or a fragment of a geneticvariation. Such oligonucleotides or nucleic acids can be designed usingthe methods described herein. In some embodiments, the kit comprises oneor more labeled nucleic acids capable of allele-specific detection ofone or more specific polymorphic markers or haplotypes with a geneticvariation, and reagents for detection of the label. In some embodiments,a kit for detecting SNP markers can comprise a detection oligonucleotideprobe, that hybridizes to a segment of template DNA containing a SNPpolymorphism to be detected, an enhancer oligonucleotide probe,detection probe, primer and/or an endonuclease, for example, asdescribed by Kutyavin et al., (Nucleic Acid Res. 34:e128 (2006)). Inother embodiments, the kit can contain reagents for detecting SNVsand/or CNVs.

In some embodiments, the DNA template is amplified by any means of thepresent disclosure, prior to assessment for the presence of specificgenetic variations as described herein. Standard methods well known tothe skilled person for performing these methods can be utilized, and arewithin scope of the disclosure. In one such embodiment, reagents forperforming these methods can be included in the reagent kit.

In a further aspect of the present disclosure, a pharmaceutical pack(kit) is provided, the pack comprising a therapeutic agent and a set ofinstructions for administration of the therapeutic agent to humansscreened for one or more variants of the present disclosure, asdisclosed herein. The therapeutic agent can be a small molecule drug, anantibody, a peptide, an antisense or RNAi molecule, or other therapeuticmolecules as described herein. In some embodiments, an individualidentified as a non-carrier of at least one variant of the presentdisclosure is instructed to take the therapeutic agent. In one suchembodiment, an individual identified as a non-carrier of at least onevariant of the present disclosure is instructed to take a prescribeddose of the therapeutic agent. In some embodiments, an individualidentified as a carrier of at least one variant of the presentdisclosure is instructed not to take the therapeutic agent. In someembodiments, an individual identified as a carrier of at least onevariant of the present disclosure is instructed not to take a prescribeddose of the therapeutic agent. In some embodiments, an individualidentified as a carrier of at least one variant of the presentdisclosure is instructed to take an agent that targets the JC Virus. Forexample, an individual identified as a carrier of at least one variantof the present disclosure can be instructed to take an agent thattargets the JC Virus prior to or in conjunction with, taking animmunosuppressive agent.

Also provided herein are articles of manufacture, comprising a probethat hybridizes with a region of human chromosome as described hereinand can be used to detect a polymorphism described herein. For example,any of the probes for detecting polymorphisms or genetic variationsdescribed herein can be combined with packaging material to generatearticles of manufacture or kits. The kit can include one or more otherelements including: instructions for use; and other reagents such as alabel or an agent useful for attaching a label to the probe.Instructions for use can include instructions for screening applicationsof the probe for making a diagnosis, prognosis, or theranosis to PML ina method described herein. Other instructions can include instructionsfor attaching a label to the probe, instructions for performing in situanalysis with the probe, and/or instructions for obtaining a nucleicacid sample to be analyzed from a subject. In some cases, the kit caninclude a labeled probe that hybridizes to a region of human chromosomeas described herein.

The kit can also include one or more additional reference or controlprobes that hybridize to the same chromosome or another chromosome orportion thereof that can have an abnormality associated with aparticular endophenotype. A kit that includes additional probes canfurther include labels, e.g., one or more of the same or differentlabels for the probes. In other embodiments, the additional probe orprobes provided with the kit can be a labeled probe or probes. When thekit further includes one or more additional probe or probes, the kit canfurther provide instructions for the use of the additional probe orprobes. Kits for use in self-testing can also be provided. Such testkits can include devices and instructions that a subject can use toobtain a nucleic acid sample (e.g., buccal cells, blood) without the aidof a health care provider. For example, buccal cells can be obtainedusing a buccal swab or brush, or using mouthwash.

Kits as provided herein can also include a mailer (e.g., a postage paidenvelope or mailing pack) that can be used to return the nucleic acidsample for analysis, e.g., to a laboratory. The kit can include one ormore containers for the nucleic acid sample, or the nucleic acid samplecan be in a standard blood collection vial. The kit can also include oneor more of an informed consent form, a test requisition form, andinstructions on how to use the kit in a method described herein. Methodsfor using such kits are also included herein. One or more of the forms(e.g., the test requisition form) and the container holding the nucleicacid sample can be coded, for example, with a bar code for identifyingthe subject who provided the nucleic acid sample.

In some embodiments, an in vitro screening test can comprise one or moredevices, tools, and equipment configured to collect a nucleic acidsample from an individual. In some embodiments of an in vitro screeningtest, tools to collect a nucleic acid sample can include one or more ofa swab, a scalpel, a syringe, a scraper, a container, and other devicesand reagents designed to facilitate the collection, storage, andtransport of a nucleic acid sample. In some embodiments, an in vitroscreening test can include reagents or solutions for collecting,stabilizing, storing, and processing a nucleic acid sample.

Such reagents and solutions for nucleotide collecting, stabilizing,storing, and processing are well known by those of skill in the art andcan be indicated by specific methods used by an in vitro screening testas described herein. In some embodiments, an in vitro screening test asdisclosed herein, can comprise a microarray apparatus and reagents, aflow cell apparatus and reagents, a multiplex nucleotide sequencer andreagents, and additional hardware and software necessary to assay anucleic acid sample for certain genetic markers and to detect andvisualize certain genetic markers.

The present disclosure further relates to kits for using antibodies inthe methods described herein. This includes, but is not limited to, kitsfor detecting the presence of a variant polypeptide in a test nucleicacid sample. One preferred embodiment comprises antibodies such as alabeled or labelable antibody and a compound or agent for detectingvariant polypeptides in a nucleic acid sample, means for determining theamount or the presence and/or absence of variant polypeptide in thenucleic acid sample, and means for comparing the amount of variantpolypeptide in the nucleic acid sample with a standard, as well asinstructions for use of the kit. In certain embodiments, the kit furthercomprises a set of instructions for using the reagents comprising thekit.

Computer-Implemented Aspects

As understood by those of ordinary skill in the art, the methods andinformation described herein (genetic variation association with PML)can be implemented, in all or in part, as computer executableinstructions on known computer readable media. For example, the methodsdescribed herein can be implemented in hardware. Alternatively, themethod can be implemented in software stored in, for example, one ormore memories or other computer readable medium and implemented on oneor more processors. As is known, the processors can be associated withone or more controllers, calculation units and/or other units of acomputer system, or implanted in firmware as desired. If implemented insoftware, the routines can be stored in any computer readable memorysuch as in RAM, ROM, flash memory, a magnetic disk, a laser disk, orother storage medium, as is also known. Likewise, this software can bedelivered to a computing device via any known delivery method including,for example, over a communication channel such as a telephone line, theInternet, a wireless connection, etc., or via a transportable medium,such as a computer readable disk, flash drive, etc.

More generally, and as understood by those of ordinary skill in the art,the various steps described above can be implemented as various blocks,operations, tools, modules and techniques which, in turn, can beimplemented in hardware, firmware, software, or any combination ofhardware, firmware, and/or software. When implemented in hardware, someor all of the blocks, operations, techniques, etc. can be implementedin, for example, a custom integrated circuit (IC), an applicationspecific integrated circuit (ASIC), a field programmable logic array(FPGA), a programmable logic array (PLA), etc.

Results from such genotyping can be stored in a data storage unit, suchas a data carrier, including computer databases, data storage disks, orby other convenient data storage means. In certain embodiments, thecomputer database is an object database, a relational database or apost-relational database. Data can be retrieved from the data storageunit using any convenient data query method.

When implemented in software, the software can be stored in any knowncomputer readable medium such as on a magnetic disk, an optical disk, orother storage medium, in a RAM or ROM or flash memory of a computer,processor, hard disk drive, optical disk drive, tape drive, etc.Likewise, the software can be delivered to a user or a computing systemvia any known delivery method including, for example, on a computerreadable disk or other transportable computer storage mechanism.

The steps of the claimed methods can be operational with numerous othergeneral purpose or special purpose computing system environments orconfigurations. Examples of well known computing systems, environments,and/or configurations that can be suitable for use with the methods orsystem of the claims include, but are not limited to, personalcomputers, server computers, hand-held or laptop devices, multiprocessorsystems, microprocessor-based systems, set top boxes, programmableconsumer electronics, network PCs, minicomputers, mainframe computers,distributed computing environments that include any of the above systemsor devices, and the like.

The steps of the claimed method and system can be described in thegeneral context of computer-executable instructions, such as programmodules, being executed by a computer. Generally, program modulesinclude routines, programs, objects, components, and/or data structuresthat perform particular tasks or implement particular abstract datatypes. The methods and apparatus can also be practiced in distributedcomputing environments where tasks are performed by remote processingdevices that are linked through a communications network. In bothintegrated and distributed computing environments, program modules canbe located in both local and remote computer storage media includingmemory storage devices. Numerous alternative embodiments could beimplemented, using either current technology or technology developedafter the filing date of this application, which would still fall withinthe scope of the claims defining the disclosure.

While the risk evaluation system and method, and other elements, havebeen described as preferably being implemented in software, they can beimplemented in hardware, firmware, etc., and can be implemented by anyother processor. Thus, the elements described herein can be implementedin a standard multi-purpose CPU or on specifically designed hardware orfirmware such as an application-specific integrated circuit (ASIC) orother hard-wired device as desired. When implemented in software, thesoftware routine can be stored in any computer readable memory such ason a magnetic disk, a laser disk, or other storage medium, in a RAM orROM of a computer or processor, in any database, etc. Likewise, thissoftware can be delivered to a user or a screening system via any knownor desired delivery method including, for example, on a computerreadable disk or other transportable computer storage mechanism or overa communication channel, for example, a telephone line, the internet, orwireless communication. Modifications and variations can be made in thetechniques and structures described and illustrated herein withoutdeparting from the spirit and scope of the present disclosure.

Unless otherwise explained, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this disclosure belongs. The followingreferences contain embodiments of the methods and compositions that canbe used herein: The Merck Manual of Diagnosis and Therapy, 18th Edition,published by Merck Research Laboratories, 2006 (ISBN 0-911910-18-2);Benjamin Lewin, Genes IX, published by Jones & Bartlett Publishing, 2007(ISBN-13: 9780763740634); Kendrew et al., (eds.), The Encyclopedia ofMolecular Biology, published by Blackwell Science Ltd., 1994 (ISBN0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology andBiotechnology: a Comprehensive Desk Reference, published by VCHPublishers, Inc., 1995 (ISBN 1-56081-569-8).

Standard procedures of the present disclosure are described, e.g., inManiatis et al., Molecular Cloning: A Laboratory Manual, Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y., USA (1982); Sambrooket al., Molecular Cloning: A Laboratory Manual (2 ed.), Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y., USA (1989); Davis etal., Basic Methods in Molecular Biology, Elsevier Science Publishing,Inc., New York, USA (1986); or Methods in Enzymology: Guide to MolecularCloning Techniques Vol. 152, S. L. Berger and A. R. Kimmerl (eds.),Academic Press Inc., San Diego, USA (1987)). Current Protocols inMolecular Biology (CPMB) (Fred M. Ausubel, et al., ed., John Wiley andSons, Inc.), Current Protocols in Protein Science (CPPS) (John E.Coligan, et al., ed., John Wiley and Sons, Inc.), Current Protocols inImmunology (CPI) (John E. Coligan, et al., ed. John Wiley and Sons,Inc.), Current Protocols in Cell Biology (CPCB) (Juan S. Bonifacino etal., ed., John Wiley and Sons, Inc.), Culture of Animal Cells: A Manualof Basic Technique by R. Ian Freshney, Publisher: Wiley-Liss; 5thedition (2005), and Animal Cell Culture Methods (Methods in CellBiology, Vol. 57, Jennie P. Mather and David Barnes editors, AcademicPress, 1 st edition, 1998), which are all incorporated by referenceherein in their entireties.

It should be understood that the following examples should not beconstrued as being limiting to the particular methodology, protocols,and compositions, etc., described herein and, as such, can vary. Thefollowing terms used herein is for the purpose of describing particularembodiments only, and is not intended to limit the scope of theembodiments disclosed herein.

Disclosed herein are molecules, materials, compositions, and componentsthat can be used for, can be used in conjunction with, can be used inpreparation for, or are products of methods and compositions disclosedherein. It is understood that when combinations, subsets, interactions,groups, etc. of these materials are disclosed and while specificreference of each various individual and collective combinations andpermutation of these molecules and compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a nucleotide or nucleic acid is disclosed and discussed anda number of modifications that can be made to a number of moleculesincluding the nucleotide or nucleic acid are discussed, each and everycombination and permutation of nucleotide or nucleic acid and themodifications that are possible are specifically contemplated unlessspecifically indicated to the contrary. This concept applies to allaspects of this application including, but not limited to, steps inmethods of making and using the disclosed molecules and compositions.Thus, if there are a variety of additional steps that can be performedit is understood that each of these additional steps can be performedwith any specific embodiment or combination of embodiments of thedisclosed methods, and that each such combination is specificallycontemplated and should be considered disclosed.

Those skilled in the art can recognize, or be able to ascertain using nomore than routine experimentation, many equivalents to the specificembodiments of the method and compositions described herein. Suchequivalents are intended to be encompassed by the following claims.

It is understood that the disclosed methods and compositions are notlimited to the particular methodology, protocols, and reagents describedas these can vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to limit the scope of the present disclosure which canbe limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the meanings that would be commonly understood by one of skill inthe art in the context of the present specification.

It should be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural reference unless thecontext clearly dictates otherwise. Thus, for example, reference to “anucleotide” includes a plurality of such nucleotides; reference to “thenucleotide” is a reference to one or more nucleotides and equivalentsthereof known to those skilled in the art, and so forth.

The term “and/or” shall in the present context be understood to indicatethat either or both of the items connected by it are involved. Whilepreferred embodiments of the present disclosure have been shown anddescribed herein, it can be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions can now occur to those skilled inthe art without departing from the disclosure. It should be understoodthat various alternatives to the embodiments of the disclosure describedherein can be employed in practicing the disclosure. It is intended thatthe following claims define the scope of the disclosure and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

EXAMPLES Example 1—Experimental Approach

In the present study, a set of genes were identified, deleteriousvariants within which increase susceptibility to PML. The relevant geneswere discovered on the basis of a combined CNV plus sequence analysisapproach. Two sets of genes were compiled (see Table 6 and correspondingdescription):

-   -   A. A set based on a detailed literature review of genes involved        in the immune system and JC virus biology, along with genes        described in the context of PML via case reports.    -   B. A set based on the observation of rare CNVs within the PML        cohort.

A non-redundant list of 419 genes was generated (see Table 6), whichcontains 245 curated from immune deficiency (immunodeficiency) reviews(Table 6, ‘Public db’), 169 identified via rare CNVs using the methodsdescribed herein (Table 6, ‘PBio’), and 6 genes that were found usingboth methods (Table 6, ‘Both’). See Table 6 and description below forfurther information).

Using this set of 419 genes, it was determined whether:

-   -   Rare CNVs were present that might explain the susceptibility to        PML;    -   Rare sequence variants (determined via whole exome sequencing        analysis—WES) were present that might explain the susceptibility        to PML;    -   Combinations of CNVs, SNVs and/or CNVs and SNVs might explain        the susceptibility;    -   Individual variants might be present at higher frequency in the        PML cohort (variant burden analysis—Tables 14, 15);    -   Total numbers of heterozygous, damaging variants were high for        any specific genes (gene burden analysis—Table 13).

In all cases, due consideration was given to:

-   -   Pathogenic/deleterious nature of the variants observed (e.g.,        whether gene function was highly likely to be affected);    -   Rarity of the variants or variant combinations (e.g., those that        would be expected to be present in 1% or less of the normal        population were considered);    -   Ethnicity of the PML cases to account for potential frequency        differences in one population subgroup vs. another. Ethnicities        (e.g., ancestry) for the PML patients are reported in Table 7.        For Sample ID identifiers beginning with ‘MVGS’, ethnicities        were not reported but all patients were from the USA and their        ethnicities were assumed to be of European (EUR) ancestry.        However, PML case MVGS811-13a is potentially of African (AFR)        ancestry on the basis of common SNVs that are also found in PML        cases known to be of AFR ancestry. In one embodiment,        ethnic-specific frequency data from the ExAC database was used        to assess relative frequencies of variants found in PML patients        vs. an unselected population (ExAC subjects). ExAC ethnicities        were designated as follows: African/African American (AFR),        Latino (LAT, also known as AMR), East Asian (EAS), Finnish        (FIN), Non-Finnish European (EUR, also known as NFE), South        Asian (SAS), and Other (OTH). For some PML cases reported in        Table 7, the ethnicities were alternately reported as        Subsaharan, North African (MGB), Caribbean (CAR), or Hispanic        (HISP). For interpretation of variants found in these patients,        the assignments of ancestry using ExAC db designations were as        follows: AFR=MGB or Subsaharan; LAT=CAR or HISP. Ancestry was        unknown for two PML cases (PMLO2 and PML28) and, for frequency        interpretation purposes (using ExAC db), they were assumed to be        of European (EUR) ancestry.

While the primary genetic mechanism that was considered was autosomalrecessive (AR) inheritance, a number of solutions were based onautosomal dominant (AD) inheritance but only in cases for which priorevidence was found that heterozygous variants in the relevant gene hadpreviously been associated with an immune deficiency syndrome. It can beappreciated by those skilled in the art that some genes may contain bothAR and AD model pathogenic variants (e.g., see Table 6 entries marked as‘AD AR’ in the ‘Disease Model’ column).

For AR inheritance (˜40% of genes in Table 6 fall into this category, ARor AD AR), the following were considered:

-   -   Homozygous or compound heterozygous gene-disruptive CNVs;    -   Homozygous or compound heterozygous sequence variants; e.g.        single nucleotide variants (SNVs). Compound heterozygosity was        only inferred when either phasing was available or one of the        pairs of SNVs was itself homozygous;    -   Compound heterozygosity for a CNV and SNV. Such calls were only        possible in cases for which the SNV was in trans to a deletion        (e.g., DUSP16 SNV in Table 10 and the CNV in Table 1).

Example 2—Copy Number Variant (CNV) Analysis

The data presented herein was generated on the basis of a comparison ofcopy number variants (CNVs) identified in 2 cohorts:

-   -   1) 1,005 Normal individuals (Normal Variation Engine—NVE);    -   2) 71 Progressive Multifocal Leukoencephalopathy (PML) cases        along with 6 Human Immunodeficiency Virus (HIV) cases without a        diagnosis of PML (in order to aid in distinguishing germline        variants vs. acquired variants that result from HIV infection).        Total cohort size=77.

Genomic DNA Sample Hybridization—NVE and PML, HIV Cohorts

Genomic DNA samples from individuals within the Normal cohort (NVE‘test’ subjects, also referred to as ‘NVE cases’ in some tables herein)and from the PML, HIV cohort (PML, HIV ‘test’ subjects) were hybridizedagainst a single, sex-matched reference individual. Reference DNAsamples were labeled with Cy5 and test subject DNA samples were labeledwith Cy3. After labeling, samples were combined and co-hybridized toAgilent 1M feature oligonucleotide microarrays, design ID 021529(Agilent Product Number G4447A) using standard conditions (arrayComparative Genomic Hybridization—aCGH). Post-hybridization, arrays werescanned at 2 μm resolution, using Agilent's DNA microarray scanner,generating tiff images for later analysis.

All tiff images were analyzed using Agilent Feature Extraction (FE)software, with the following settings:

-   -   Human Genome Freeze: hg18: NCBI36: March 2006    -   FE version: 10.7.3.1    -   Grid/design file: 021529 D F 20091001    -   Protocol: CGH 107 September 09

This procedure generates a variety of output files, one of which is atext-tab delimited file, containing ˜1,000,000 rows of data, eachcorresponding to a specific feature on the array. This *.txt file wasused to perform CNV calling using DNAcopy, an open source softwarepackage implemented in R via BioConductor(http://www.bioconductor.org/packages/release/bioc/html/DNAcopy.html).Heterozygous losses (het loss), homozygous losses (hom loss) or gainswere determined according to a threshold log 2 ratio, which was set at:

-   -   hom loss min=−1000;    -   hom loss max=−2;    -   het loss min=−2;    -   het loss max=−0.5;    -   gain min=0.5;    -   gain max=1000;

With very few exceptions, all CNVs with a log 2 ratio value between −0.5and +0.5 were not considered. All log 2 ratio values were determinedaccording to Cy3/Cy5 (Test/Reference). A minimum probe threshold forCNV-calling was set at 2 (2 consecutive probes were sufficient to call aCNV). A CNV list was generated for each individual in the 3 cohorts(NVE, PML, and HIV).

Using custom scripts, CNVs identified in the NVE and PML cohorts (manyof which appeared in multiple individuals) were (separately) ‘merged’into master lists of non-redundant CNV-subregions, according to thepresence or absence of the CNV-subregion in individuals within thecohort. Using this approach, the NVE-master lists have:

-   -   7778 het loss    -   653 hom loss    -   4862 gain        distinct CNV-subregions, respectively. The PML+HIV cohort of 77        individuals master lists contained:    -   2523 het loss    -   314 hom loss    -   1639 gain        distinct CNV-subregions, respectively.

Those skilled in the art can appreciate that CNVs can be acquired in anindividual's genome that are not inherited. Such ‘acquired CNVs’ oftenoccur in a tissue specific manner, such as in solid tumors compared to apatient's normal tissue. In blood-derived genomic DNA samples, which arewhat was used for both the NVE and PML subjects in the studies describedherein, acquired CNVs can be the result of blood cancers such asleukemia and lymphoma, but also due to HIV infection. Many of the PMLcases in this study had HIV as their primary disease (see Table 7). Inorder to aid in the interpretation of acquired vs. germline CNVs, an HIVsub-cohort of 6 cases was included in the primary, genome-wide CNVcomparison but rare CNVs in the 6 HIV (non-PML) cases were notconsidered as relevant to PML susceptibility. The purpose of generatingdata on the 6 HIV cases was to determine whether some changes seen inPML patients who developed the disorder on a background of HIV (PML/HIV)were likely related to the underlying HIV and not the PML susceptibilityitself. In other words, the HIV cases served as a general control forthe large number of PML/HIV cases.

For example, consider 3 individuals within the NVE cohort with thefollowing hypothetical CNVs:

Chr1:1-100,000; Chr1:10,001-100,000; and Chr1:1-89,999. In the masterlist, these would be merged into 3 distinct CNV subregions, as follows:

CNV-subregion 1 Chr1:1-10,000 Subjects A, C CNV-subregion 2Chr1:10,001-89,999 Subjects A, B, C CNV-subregion 3 Chr90,000:1-100,000Subjects A, BComparison of the corresponding NVE and PML master lists ofCNV-subregions was performed (het loss versus het loss, hom loss versushom loss and gain versus gain), resulting in a combined file with totalsfor NVE and PML for each distinct CNV-subregion in the study.

The data are subsequently curated as follows (The example calculationbelow was based on an original PML cohort of 80 cases, of which 6 arenon-PML HIV controls and 3 PML cases that were duplicate samples. Insome instances, the OR and FET values reported in Table 2 were used as‘relative’ guidelines when considering the relevance of a CNV. In nearlyall instances, a CNV was considered as a potential cause or contributingfactor to PML if it was absent from the NVE database of CNVs).

-   -   Annotation using custom designed scripts in order to attach        relevant information to each CNV region regarding overlap with        known genes and exons, overlap with genes involved in the immune        system and overlap with regulatory regions, including        transcription factor binding sites.    -   A calculation of the odds ratio (OR) and Fisher's Exact test        (FET) for each CNV-subregion, according to the following        formula:

OR=(PML/(77−PML))/(NVE/(1005−NVE))

-   -   -   where:        -   PML=number of PML individuals with CNV-subregion of interest        -   NVE=number of NVE individuals with CNV-subregion of interest

As an illustrative example, consider the CNV subregion gain involvingchr2:55764753-55771586, which is found in 3 individuals in the PMLcohort and 1 individual in the NVE cohort (see Table 2). The OR is:(3/74)/(1/1004)=40.7

Note that, by one convention, if either of NVE or PML=0, a value of 0.5is added to all 4 entries in the main formula above, in order to avoiddealing with infinities (see Decks and Higgins, Statistical algorithmsin Review Manager 5, Statistical Methods Group of The CochraneCollaboration, (2010)). This has the effect of artificially lowering ORvalues in cases where no individuals within the NVE have the CNV. Thismethod is applicable to all the calculations in Table 2. This method isalso used when calculating the Fisher's 2-tailed Exact Test (FET) in theevent that any one of the variables is zero. For convenience inanalysis, the sub-cohort of 6 HIV (non-PML) cases were retained in Table2. Therefore, the OR values reported in Table 2 are slightly differentfrom the OR calculations for the actual number of PML cases (n=71).Using the example above for a CNV-subregion gain involvingchr2:55764753-55771586, the actual OR using 71 PML cases vs. 1005 NVEsubjects was: (3/68)/(1/(1004)=44.29. In some instances, a non-PML HIVcontrol (see Table 11, identified as 3280, 3281, 3283, 3284, 3285, and3286) is found to have a CNV of potential relevance in PML subjects.This can also impact the OR calculation. For example, for CNV-subregionloss chr19:55247874-55250186 the OR in Table 2 is listed as 17.38 butone case is a non-PML HIV control (Table 11, PML70 control=3280). Forthis example, the actual OR using 71 PML cases vs. 1005 NVE subjects,and excluding the non-PML HIV case, was: (4/67)/(4/(1001)=14.94.

The CNV-subregions/genes that are listed herein (e.g., in one or more ofTables 1-4), fulfill one of the following criteria:

-   -   Strong biology linking the gene that a CNV-subregion impacts or        is near, with known immune deficiency pathways/mechanisms or        biology in PML (e.g., JC virus related biology). That is, in        some cases, statistical evidence is lacking but does not exclude        the CNV-subregion as a candidate;    -   Statistical analysis combined with medium to strong biology        (e.g., links in the peer-reviewed literature to PML, JC virus,        host defense, immune deficiency, or neuropathology) without        obvious biological connection (best FET in this category was        3.25E-10);

It can be appreciated by those skilled in the art that the number of PMLcandidate CNV-subregions, irrespective of category, may increase ordecrease as additional PML cohorts are analyzed.

Example 3—Whole Exome Sequencing (WES) and Case Level Analysis

WES data was obtained on a total of 70 PML cases (non-PML HIV cases werenot sequenced—they were used simply to help in the interpretation ofcomplex CNVs observed in PML patients who also had HIV).

Variant annotation reports were further interrogated against the fullset of genes detailed above. Synonymous variants and variants predictedto be modifiers (outside coding regions) were not considered. For allother variants, further filtering was performed so that only thosepredicted by at least one in silico prediction algorithm (e.g.,Polyphen2, SIFT, MutationTaster) to be pathogenic were considered forfurther evaluation. Finally, only variants or variant combinations thatwould be expected to be present in 1% or less of the normal populationwere evaluated for case level analysis (Tables 7-10). Data from theExome Aggregation Consortium (ExAC) was used to obtain ethnic-specificfrequency data for variants under consideration (see, Lek et al.,Nature, 17; 536(7616):285-91) (2016)).

Example 4—Description of Sequence Data

The sequence file 56969-701.601 ST25.txt contains genomic sequenceinformation for (in the following order):

-   -   A. All distinct CNVs listed in Table 1;    -   B. The full genomic extent of the transcripts listed in Table 4;    -   C. Sequence variants detailed in Table 5.    -   D. The full genomic extent of the transcripts listed in Table 12

Note that:

-   -   1. SEQ ID 1-172 are the CNV sequences from Table 1;    -   2. SEQ ID 173-455 are the transcript sequences from Table 4;    -   3. SEQ ID 1000-1329 are the sequence variants from Table 5;    -   4. SEQ ID 1500-2177 are the transcript sequences from Table 12.

Examples of Sequences Submitted

Sequence entry starts:

TABLE 1 SEQ ID 1 = 49,653bp CNV (het loss) at chr1:1086119-1135772involving genes MIR200A, MIR200B, MIR429, TNFRSF18, TTLL10: <210> 1<211> 49654 <212> DNA <213> Homo sapiens <400> 1cttctggggt ctaaggccag aagtgacctt tcttctcacg gaggcacccc cacatcacag 60gccccaagct cccaccagga gtccccaggc agcaggtttt ccaccacagc cgggaagagc 120cccgccttca ccacccacca ccagccaatc ccgagaccac cgaagccccc agaccgggcc 180.................................(sequence truncated for brevity)gattcccgca cggccgggga cggccccagg gccttgggag cgtctgtgga cacctgtggt 49560gtgggccgag gagctgggag ctcatctgaa cacgccagca ctcgcgcatc cacgctgctg 49620gcggatgcct gggtttctcc actgtggggc cacg 49654Sequence entry ends.Sequence entry starts:

TABLE 4 SEQ ID 173 = MIR200B, transcript NR 029639,which is 95bp in length: <210> 173 <211>95 <212> DNA <213> Homo sapiens<400> 173ccagctcggg cagccgtggc catcttactg ggcagcattg gatggagtca ggtctctaat 60actgcctggt aatgatgacg gcggagccct gcacg 95Sequence entry ends.Sequence entry starts:

TABLE 5 SEQ ID 1148 = chr 9:304628 referenceallele = G; alternate allele = A <210> 1148 <211> 40 <212> DNA<213> Homo sapiens <220> <221> variant <222> (20) .. (20) <223> G->A<400> 1148 tttaaaaaga ctggatctcg aaaagatttt cacaagacgc 40Sequence entry ends.Sequence entry starts:

TABLE 12 SEQ ID 1500 = ACADM, transcript NM 000016,which is 39,313 bp in length: <210> 1500 <211> 39313 <212> DNA<213> Homo sapiens <400> 1500cgcaagtecc cccaccgtte agegcaaceg ggccctccca gccccgccge cgtccccctc 60ccccgccctg getctctttc cgcgctgegg teagcctegg cgtcccacag agagggccag 120.................................(sequence truncated for brevity)gtaatagtgt atatttettg tatttactat gatgaaaaaa ggtegtttta attttgaatt 39240gaataaagtt acctgttcat tttttattag atattttaaa gacttcagaa aatataaata 39300tgaaataatt taa 39313Sequence entry ends.

Example 5

Those skilled in the art can appreciate that genes can be impacted byacquired or germline genetic variants (e.g., CNVs), wherein each genehas the potential to contain genetic variants that are acquired (e.g.,via a disease process such as HIV infection, or cancers such as leukemiaand lymphoma) or present in the germ line (e.g., inherited from a parentor are de novo, e.g. not inherited from a parent). In FIG. 1 , the PRKCBgene was impacted by germ line variants in 2 PML cases and acquiredvariants in 6 PML cases. The invention described herein is focused ondetection of germline variants that are present in PML patient genomes.Therefore, no solutions/explanations for a given patient's PML was basedon an acquired CNV, although another PML patient could potentially be‘solved’ by one or two germline rare variants impacting the gene.

For this PRKCB example, no CNV-based solutions were found (an AR modelwas assumed), but 1 SNV solution is reported in Table 8 (het SNV, an ADmodel is assumed for this PML case). Further supporting evidence wasassessed for the PRKCB gene by performing String analysis (highconfidence=0.7, 1 st shell=up to 10 interactors; string-db.org; seeSzklarczyk et al., (2015), and references therein). String analysisshowed that PRKCB interacts with PML-419 genes CARD11, IKBKB, and RBCK1(see Table 6).

In FIG. 2 , both TNFRSF13C and CENPM are disrupted and/or gained by aset of acquired CNV gains. Acquired CNVs can be very complex, such asthe high copy number gains often identified in tumor-derived DNA samples(as compared to the patient's normal genome). In the PML gene discoverydescribed herein, blood-derived genomic DNA obtained from severalPML-diagnosed HIV patients, or PML cases with a primary disease ofleukemia and lymphoma (reported as ‘Other’ in Table 7), showed complexgenomic changes (e.g., gains exhibiting a dup-trip-dup pattern). In somePML cases, the acquired gains passed the log 2 ratio cutoff (>0.5) thatwas selected for this study, but in other PML cases the log 2 ratios forthe gains were <0.5 and this data was filtered out from the mainanalyses that were performed to ascertain rare germline CNVs.

In one embodiment of the invention, a set of 6 non-PML HIV cases (3African ancestry, 3 European ancestry) were used to aid in theinterpretation of whether a CNV was an acquired or germline event. Thenon-PML ‘PML cases’ are labeled with ‘ control’ in Table 11 andcorrespond to ‘PML Case ID’ numbers 3280, 3281, 3283, 3284, 3285, and3286. While some CNVs are reported in Tables 1 and 2 for this set ofnon-PML control HIV subjects, none of these genetic findings were usedto nominate a gene discovered on the basis of rare CNVs (as compared tothe NVE db) as a potential PML gene (PBio genes reported in Table 6). Inother words, these rare CNVs were only used to aid in determining if aparticular genomic region containing multiple overlapping CNVs waspotentially due to an acquired genetic event. Those skilled in the artcan appreciate that the set of experiments described herein do notnecessarily fully rule in or out that a given genomic region containedonly acquired CNVs vs. only germline CNVs (e.g. it's possible that thesame region can contain an acquired CNV in one individual and a germlineCNV in another).

For the CNV data shown in FIG. 2 , both the TNFRSF13C and CENPM geneswere included in PML-419 gene list (Table 6) on the basis of theirimmune or neurological related biology reported in the literature. NoCNV or SNV PML solutions were found for these two genes, but Stringanalysis (high confidence=0.7, 1st shell=up to 10 interactors) showsthat TNFRSF13C interacts with PML-419 genes TRAF3 (Table 7 solution) andTNFRSF13B (Table 8 solution), as well as BTK (a known PML gene, seeTable 6).

FIG. 3 shows another example of a gene that is impacted by both germlineand acquired CNVs. While no PML cases were solved on the basis of theacquired or germline CNVs shown to impact the PKHD1 gene, nomination ofthis gene to Table 6 on the basis of its biology resulted in finding 3potential alternate solutions (AR model) for 3 other PML cases (seeTable 8). However, String analysis (high confidence=0.7, 1st shell=up to10 interactors) did not reveal any PML-419 gene interactions with PKHD1.

Example 6

Those skilled in the art can appreciate that an AR disease model wouldinvolve ascertaining whether both alleles (for a gene or genetic locus)are impacted by a genetic variant in individuals affected by thedisorder. The types of genetic variants can be SNVs, CNVs, indels, etc.In the study describe herein, if an AR disease model was invoked for agene (see Table 6), we assessed the PML patient's CGH data for CNVs(heterozygous or homozygous) and their exome data for SNVs (heterozygousor homozygous). Thus, each patient may be solved for one of the PML-419genes (Table 6) with one of the following scenarios: homozygousdeletion, homozygous duplication (log 2 ratio will appear comparable tothat typically found for triplications), homozygous SNV, compoundheterozygous SNVs, compound heterozygous CNVs, or compound heterozygousSNV and CNV. Those skilled in the art know that, for an AR diseasemechanism, a pathogenic SNV or CNV may have appreciable frequency in thegeneral population (e.g., up to 1% frequency) with little to no impacton the individual's health, but when present with a second pathogenicvariant on the other allele, can cause disease.

FIG. 4 shows an example of an intronic loss impacting the BMPR2 gene.Patient PML29 was found to have a homozygous deletion, whereas aspatients PML58 and MVGS811-13a have a heterozygous deletion. Assuming anAR disease model, no SNV solutions were found for this gene; however,PML29 is potentially solved due to the homozygous deletion that wasdetected. While immune-related biology is reported for studies on BMPR2(see Table 6), String analysis (high confidence=0.7, 1st shell=up to 10interactors) did not reveal any PML-419 gene interactions with BMPR2.

FIG. 5 shows an example of an exonic gain that disrupts the COMMD6 gene.Two PML patients were found to have homozygous duplications of this CNV.Interestingly, while String analysis (high confidence=0.7, 1st shell=upto 10 interactors) did not reveal any PML-419 gene interactions withCOMMD6, recent studies (see Table 6, PMIDs 25355947 and 27441653) show apotential link between COMMD6 and known PML gene WAS via the WASH gene.

FIG. 6 shows an example of an exonic gain that disrupts the KCTD7 geneand its right breakpoint is upstream of RABGEF1 (e.g. one or both genesmay be causing/contributing to PML). A recently annotated non-coding RNA(see hg19 assembly, LOC100996437) may also be impacted by this CNV. Bothgenes have immune and neurological links (see Table 6) and since patientPML29 has a homozygous duplication, it was added as a PML solution inTable 7. String analysis (high confidence=0.7, 1st shell=up to 10interactors) did not reveal any PML-419 gene interactions for eithergene, but they are linked together in a joint String analysis.

FIG. 7 shows an example of a gain that disrupts FPR2 (left breakpoint)and ZNF616 (right breakpoint, gene not labeled), and other genes arefully encompassed by this CNV. There is strong supporting biology forFPR2 (see Table 6) and it is listed as a PML solution in Table 7. Stringanalysis (high confidence=0.7, 1st shell=up to 10 interactors) did notreveal any PML-419 gene interactions for FPR2, but a joint analysis ofTable 7 genes did reveal an interaction (see FIG. 13 ).

FIG. 8 shows an example of an exonic loss impacting the PIK3CD andPIK3CD-AS1 genes. Patient MVGS811-13a has a homozygous deletion and isreported as a solution in Table 7 based on the strong immune-relatedbiology for PIK3CD (see Table 6). String analysis (high confidence=0.7,1 st shell=up to 10 interactors) reveals PML-419 gene interactions forPTEN and PIK3R1.

Example 7

A subset of the rare CNVs found in our PML study were located inintergenic regions. While those skilled in the art can appreciate thatintergenic variants (CNVs, SNVs, etc.) can have long range effects onthe expression of genes (e.g., gene regulatory elements can be locatedseveral kilobases away from the genes under their influence), in ourstudy we assumed that intergenic CNVs were potentially impacting one orboth adjacent genes if they were located <˜100 Kb away, either upstreamor downstream. The ENCODE project has revealed a wealth of information,such as transcription factor binding sites, and rare CNVs that wereidentified in the study herein were checked for their potential impacton these sites (hg19 assembly ENCODE annotation was checked) and wereoften found to impact transcription factor binding sites and/or werelocated in conserved DNA regions.

FIG. 9 shows an intergenic gain that is upstream of CD180. PatientMVGS995-4a has a homozygous duplication and, while not considered as aPML solution in Table 7, is potentially an alternate solution that maybe causing or contributing to the patient's PML based on alteredexpression of CD180. The gene has immune-related biology (see Table 6)and String analysis (high confidence=0.7, 1st shell=up to 10interactors) reveals a PML-419 gene interaction with PLCG2 (see Table 7,2 PML cases have a solution for this gene).

FIG. 10 shows an intergenic loss that is upstream of VDAC1. PatientPML30 has a homozygous deletion and, while not considered as a PMLsolution in Table 7, is potentially an alternate solution that may becausing or contributing to the patient's PML based on altered expressionof VDAC1. String analysis (high confidence=0.7, 1st shell=up to 10interactors) did not reveal any PML-419 gene interactions for VDAC1.

FIG. 11 shows an intergenic loss that is downstream of EGR1 and ETF1.Patient PML69 has a homozygous deletion and, based on links for EGR1 toPML-419 genes (Table 6) and its proximity to EGR1 (˜4 Kb away), it wasadded as a potential PML solution in Table 7. String analysis (highconfidence=0.7, 1st shell=up to 10 interactors) reveals PML-419 geneinteractions with JUN, PTEN, and TP53), but nothing of note was foundfor String analysis of ETF1.

FIG. 12 shows an intergenic loss that is upstream of ITSN2. PatientPML65 has a homozygous deletion and, based on links for ITSN2 to a knownPML gene (WAS) in the PML-419 gene list (Table 6), it was added as apotential PML solution in Table 7. Interestingly, another PML case wasfound to have a rare homozygous SNV in ITSN2, so this gene has 2 PMLsolutions reported in Table 7. String analysis (high confidence=0.7, 1stshell=up to 10 interactors) did not reveal any PML-419 geneinteractions.

Example 8

Pathway analyses, such as protein-protein interactions, are providingvaluable insights into the underlying biology for complex diseases.While PML is a very rare disease that requires several concurrentfactors (e.g., infection by the JC virus), multiple genes may beindependently causing or increasing the risk of developing thisneurodegenerative disorder based on the presence of a genetic variant ina given gene (e.g., a heterozygous variant wherein one deleteriousvariant is present on the maternally or paternally inherited allele, ahomozygous variant wherein the same deleterious variant is present onboth alleles, or compound heterozygous variants wherein a pair ofdeleterious variants are present but one is found on the maternallyinherited allele and the other is found on the paternally inheritedallele). As hypothesized, presence of an immune deficiency geneticdisorder was another prerequisite. Indeed, in the PML study describedherein, 43 genes were proposed as solutions for 61 of 71 PML cases (seeTable 7) that were assessed using array CGH and whole exome sequencing.Numerous algorithms and associated databases have been developed toinvestigate molecular pathways, such as String (see, Szklarczyk et al.,(2015), and references therein).

FIG. 13 shows an example of String analysis performed on the 43 genesconsidered as PML solutions on the basis of an AD or AR disease model. Aseries of interactions were found for 21 of 43 genes, and in severalinstances this included interactions for genes implicated in 2 or morePML cases that are reported in Table 7 (9 cases for TNFRSF11A, 4 casesfor PLCG2, 3 cases for ZAP70 and NOD2, and 2 PML cases for TICAM1).

Example 9

To determine the likelihood that a randomly selected individual wouldharbor one of the variants described herein, the following analysis wasperformed: For each variant or combination of variants, theethnic-specific frequency quoted in Table 7 was used to determine theprobability that a randomly selected individual of the same ethnicitywould be expected not to harbor the variant or combination of variants.The product of all such probabilities was calculated (e.g., theprobability that a randomly selected individual would not harbor any ofthe variants) and subtracted from 1, yielding the probability that arandom individual would harbor at least one of the variants. It wasfound that, for HIV cases, the probability of a random individualharboring at least one of the variants was ˜5%, which is consistent withthe pre-HAART risk of PML in the context of HIV. For non-HIV cases(mostly MS/NTZ), the risk was ˜ 1%, which, again, is consistent with therisk of PML in MS/NTZ, especially after long-term therapy.

These analyses support the notion that the frequencies of the variantsidentified as relevant to PML risk are consistent with the actualobserved risks for unselected individuals. The analyses are predicatedon the reasonable assumption that there is no PML-relevant connectionwith the risk of developing HIV (an acquired infection) and/or MS (e.g.,this implies that treatment of healthy individuals with Natalizumab, forexample, would result in similar risks of PML). Any deviations (e.g.,variants found in a slightly higher number of normal individuals thanexpected according to the numbers actually observed to be affected byPML) may be due to: penetrance (e.g., not everyone with the variantswill be at maximal risk of PML); the assumption that individuals withMS, HIV and other underlying conditions represented a normal (e.g., withrespect to PML risk) cross-section of the general population, prior todeveloping the underlying disorders HIV, MS etc; and under ascertainmentof PML, even in patients with HIV, MS/NTZ.

Example 10—Tables Referenced in this Study

TABLE 1 CNVs of interest in this study Original Original Original PMLRefSeq SEQ Chr CNV Start CNV Stop CNV Size CNV Type Case ID Gene SymbolID 1 1086119 1135772 49653 het loss 3009 MIR200A 1 MIR200B MIR429TNFRSF18 TTLL10 1 9634094 9635206 1112 hom loss 3009 PIK3CD 2 1 1201851212032581 14069 gain 3205 3 1 19593401 19602807 9406 het loss 3203 CAPZB4 1 21695957 21700243 4286 het loss 3161 5 1 24364786 24391166 26380gain 3199 IFNLR1 6 1 28666669 28737671 71002 gain 3161 PHACTR4 7 RCC1SNHG3 1 49372054 49380088 8034 het loss 3145 AGBL4 8 1 153816159153827698 11539 het loss 3168 9 1 205607255 205610341 3086 gain 3007 101 215760485 215762451 1966 het loss 3117 GPATCH2 11 1 215866737215869900 3163 het loss 3151 GPATCH2 12 2 10352668 10356083 3415 hetloss 3007 13 2 24457024 24462631 5607 hom loss 3204 14 2 3846871738471950 3233 het loss 3175 15 2 38516138 38524237 8099 het loss 3151 162 38726517 38731845 5328 het loss 3159 17 2 40620890 40624089 3199 hetloss 3202 18 2 46631006 46643501 12495 gain 3145 RHOQ 19 2 5576475355790559 25806 gain 3143 PNPT1 20 2 55764753 55790559 25806 gain 3193PNPT1 20 2 55764753 55790559 25806 ga?n 3282 PNPT1 20 2 5576475355790559 25806 gain 3143 PNPT1 20 2 55764753 55790559 25806 gain 3193PNPT1 20 2 55764753 55790559 25806 gain 3282 PNPT1 20 2 5576475355790559 25806 gain 3143 PNPT1 20 2 55764753 55790559 25806 gain 3193PNPT1 20 2 55764753 55790559 25806 gain 3282 PNPT1 20 2 7119067771200120 9443 het loss 3175 MCEE 21 2 71190677 71200120 9443 het loss3175 MCEE 21 2 71191311 71200120 8809 het loss 3204 MCEE 22 2 7119810871200120 2012 het loss 3143 MCEE 23 2 71190677 71200120 9443 het loss3175 MCEE 21 2 71198108 71200120 2012 het loss 3193 MCEE 23 2 7119810871200120 2012 het loss 3200 MCEE 23 2 71191311 71200120 8809 het loss3204 MCEE 22 2 74773432 74913493 140061 gain 3118 HK2 24 2 105418748105435274 16526 het loss 3193 FHL2 25 2 110182348 110210249 27901 gain3174 MALL 26 MIR4267 MIR4436B1 MIR4436B2 2 127823042 127828410 5368 hetloss 3273 27 2 134911636 134914254 2618 het loss 3273 MGAT5 28 2203005216 203019933 14717 het loss 3009 BMPR2 29 2 203005216 20301993314717 het loss 3192 BMPR2 29 2 203005216 203019933 14717 hom loss 3152BMPR2 29 2 230212897 230216339 3442 het loss 3154 DNER 30 3 122979920122994402 14482 gain 3202 IQCB1 31 4 26565071 26566345 1274 het loss3010 STIM2 32 4 26565071 26566345 1274 het loss 3125 STIM2 32 4 2656507126566345 1274 het loss 3168 STIM2 32 4 26565071 26566345 1274 het loss3282 STIM2 32 4 26565071 26566345 1274 het loss 3284 STIM2 32 4 2656507126566345 1274 hom loss 3273 STIM2 32 4 54838623 54873909 35286 gain 3153PDGFRA 33 4 90791460 90843887 52427 gain 3168 34 4 90800863 908082587395 het loss 3009 35 4 90800863 90808258 7395 het loss 3284 35 545331278 46150784 819506 gain 3157 HCN1 36 5 49771219 49774457 3238 gain3273 EMB 37 5 66619415 66636116 16701 gain 3010 38 5 78480194 7849729617102 gain 3205 39 5 78497296 78531091 33795 gain 3132 40 5 7849729678521408 24112 gain 3185 41 5 78497296 78531091 33795 gain 3132 40 578497296 78521408 24112 gain 3185 41 5 78500552 78526637 26085 gain 320542 5 78497296 78531091 33795 gain 3132 40 5 78500552 78526637 26085 gain3205 42 5 78497296 78531091 33795 gain 3132 40 5 83490494 83495169 4675het loss 3204 EDIL3 43 5 133372071 133379727 7656 hom loss 3153 44 5137836466 137843309 6843 hom loss 3279 45 5 150159466 150202601 43135het loss 3117 46 5 150159466 150204134 44668 het loss 3180 47 5150159466 150202601 43135 het loss 3199 46 5 150159466 150204134 44668het loss 3278 47 5 150159466 150202601 43135 het loss 3117 46 5150159466 150204134 44668 het loss 3180 47 5 150159466 150202601 43135het loss 3199 46 5 150159466 150204134 44668 het loss 3278 47 5150159466 150202601 43135 het loss 3117 46 5 150159466 150204134 44668het loss 3180 47 5 150159466 150202601 43135 het loss 3199 46 5150159466 150204134 44668 het loss 3278 47 5 150185190 150201145 15955hom loss 3009 48 5 150185190 150201145 15955 hom loss 3143 48 5150185190 150202601 17411 hom loss 3152 49 5 150185190 150202601 17411hom loss 3154 49 5 150185190 150202601 17411 hom loss 3193 49 5150159466 150201145 41679 hom loss 3196 50 5 150185190 150201145 15955hom loss 3281 48 5 150185190 150201145 15955 hom loss 3009 48 5150185190 150201145 15955 hom loss 3143 48 5 150185190 150202601 17411hom loss 3152 49 5 150185190 150202601 17411 hom loss 3154 49 5150185190 150202601 17411 hom loss 3193 49 5 150159466 150201145 41679hom loss 3196 50 5 150185190 150201145 15955 hom loss 3281 48 5150185190 150202601 17411 hom loss 3152 49 5 150185190 150202601 17411hom loss 3154 49 5 150185190 150202601 17411 hom loss 3193 49 5150185190 150204134 18944 het loss 3132 51 5 150159466 150204134 44668het loss 3180 47 5 150202601 150204134 1533 het loss 3196 52 5 150191322150204134 12812 het loss 3273 53 5 150185190 150204134 18944 het loss3277 51 5 150159466 150204134 44668 het loss 3278 47 5 150185190150204134 18944 het loss 3280 51 5 150185190 150204134 18944 het loss3282 51 5 179590681 179626660 35979 het loss 3172 MAPK9 54 6 28825772947403 64826 het loss 3196 DKFZP686I15217 55 NQO2 SERPINB6 6 29646462966011 1365 het loss 3193 HTATSF1P2 56 NQO2 6 51766024 51773250 7226het loss 3167 PKHD1 57 6 51952217 51969378 17161 gain 3127 PKHD1 58 651952217 51969378 17161 gain 3127 PKHD1 58 6 51953476 51965723 12247gain 3205 PKHD1 59 6 51952217 51969378 17161 gain 3127 PKHD1 58 674396294 74404837 8543 het loss 3009 SLC17A5 60 6 74396294 74398409 2115het loss 3160 SLC17A5 61 6 74396294 74404837 8543 het loss 3009 SLC17A560 6 86416979 86431527 14548 het loss 3197 62 6 91131823 91135670 3847het loss 3171 63 6 107882367 107890605 8238 het loss 3201 PDSS2 64 6166418511 166422386 3875 het loss 3125 65 6 166418511 166422386 3875 hetloss 3163 65 6 166418511 166422386 3875 het loss 3192 65 6 166418511166422386 3875 het loss 3193 65 6 166418511 166422386 3875 het loss 319465 6 166418511 166422386 3875 het loss 3200 65 6 166418511 1664223863875 het loss 3205 65 6 166418511 166422386 3875 het loss 3280 65 6166418511 166422386 3875 het loss 3281 65 6 166418511 166422386 3875 hetloss 3284 65 6 166418511 166422386 3875 hom loss 3009 65 6 166418511166422386 3875 hom loss 3152 65 6 166418511 166422386 3875 hom loss 317565 7 65741238 65768682 27444 gain 3152 KCTD7 66 7 65741238 6576868227444 gain 3202 KCTD7 66 7 157174966 157177843 2877 het loss 3009 PTPRN267 7 15742584 157496238 70397 gain 3189 PTPRN2 68 7 158000082 15802456924487 het loss 3279 PTPRN2 69 7 158000082 158024569 24487 het loss 3279PTPRN2 69 7 158000082 158024569 24487 het loss 3279 MIR595 69 PTPRN2 823103186 23125443 22257 het loss 3140 TNFRSF10A 70 8 39914488 399195945106 het loss 3126 IDO2 71 8 79905654 79910286 4632 het loss 3159 72 899790200 99799839 9639 het loss 3006 STK3 73 8 102049360 102064431 15071het loss 3173 74 8 102049360 102064431 15071 het loss 3175 74 8102049360 102064431 15071 het loss 3282 74 9 571398 584647 13249 hetloss 3006 KANK1 75 9 571398 584647 13249 het loss 3006 KANK1 75 9 580722598488 17766 het loss 3200 KANK1 76 9 580722 598488 17766 het loss 3282KANK1 76 9 580722 598488 17766 het loss 3200 KANK1 76 9 580722 59848817766 het loss 3282 KANK1 76 9 634039 637589 3550 het loss 3273 KANK1 779 634039 637589 3550 het loss 3282 KANK1 77 9 74050088 74059447 9359 hetloss 3165 GDA 78 9 93140394 93447826 307432 gain 3198 AUH 79 MIR3163MIR3910-1 MIR3910-2 NFIL3 9 118564159 118575633 11474 gain 3193 ASTN2 809 118612694 118664593 51899 het loss 3144 ASTN2 81 9 119220847 11923307812231 gain 3005 82 10 899657 1071401 171744 gain 3161 GTPBP4 83 IDI2IDI2-AS1 LARP4B 10 76217585 76411591 194006 gain 3179 KAT6B 84 10116000069 116004388 4319 gain 3010 VWA2 85 11 14677012 14689025 12013het loss 3199 PDE3B 86 11 34608313 34615878 7565 het loss 3117 EHF 87 1162382087 62398462 16375 het loss 3205 SLC3A2 88 11 76631014 7664362512611 het loss 3193 GDPD4 89 12 11616557 12422129 805572 het loss 3126ETV6 90 12 12435301 12778142 342841 het loss 3126 APOLD1 91 CDKN1BCREBL2 DUSP16 GPR19 LOH12CR1 12 12968705 12971310 2605 gain 3127 92 1291786998 94313682 2526684 het loss 3126 EEA1 93 LOC643339 12 9178699894313682 2526684 het loss 3126 LOC643339 93 MRPL42 NUDT4 NUDT4P1 SOCS2SOCS2-AS1 UBE2N 12 91786998 94313682 2526684 het loss 3126 CCDC41 93CRADD PLXNC1 12 111061085 111064486 3401 het loss 3004 TRAFD1 94 1340939924 41026908 86984 gain 3140 RGCC 95 13 75006025 75016304 10279gain 3009 COMMD6 96 13 75006025 75016304 10279 gain 3152 COMMD6 96 1391811087 91814369 3282 het loss 3143 GPC5 97 13 91811087 91811118 3 homloss 3173 GPC5 98 13 110754499 110778301 23802 gain 3006 ARHGEF7 99TEX29 14 20021118 20055469 34351 gain 3205 RNASE10 100 14 2042682420481852 55028 hom loss 3200 ECRP 101 RNASE3 14 20430810 20490129 59319het loss 3192 ECRP 102 14 20430810 20490129 59319 het loss 3192 102 1420430810 20490129 59319 het loss 3192 102 14 21096689 21105611 8922 hetloss 3125 103 14 21096689 21105611 8922 het loss 3175 103 14 2109668921105611 8922 het loss 3194 103 14 21096689 21105611 8922 het loss 3204103 14 21096689 21105611 8922 het loss 3273 103 14 21120750 211255134763 gain 3143 104 14 21120750 21125513 4763 gain 3173 104 14 6090163660909492 7856 het loss 3193 PRKCH 105 14 60912874 60921269 8395 het loss3174 PRKCH 106 14 63937192 63944459 7267 gain 3205 MTHFD1 107 1495754535 95759056 4521 het loss 3009 BDKRB2 108 14 95754535 957590564521 het loss 3173 BDKRB2 108 14 95754535 95759056 4521 het loss 3202BDKRB2 108 15 66065925 66082418 16493 het loss 3010 109 15 7043262770443017 10390 gain 3169 HEXA 110 15 75096101 75128723 32622 gain 3200PSTPIP1 111 15 75101524 75115806 14282 gain 3132 PSTPIP1 112 15 7509610175128723 32622 gain 3200 PSTPIP1 111 15 75105789 75115806 10017 gain3127 PSTPIP1 113 15 75101524 75115806 14282 gain 3132 PSTPIP1 112 1575105789 75115806 10017 gain 3199 PSTPIP1 113 15 75096101 75128723 32622gain 3200 PSTPIP1 111 15 75105789 75115806 10017 gain 3279 PSTPIP1 11315 75105789 75115806 10017 gain 3127 PSTPIP1 113 15 75101524 7511580614282 gain 3132 PSTPIP1 112 15 75105789 75115806 10017 gain 3199 PSTPIP1113 15 75096101 75128723 32622 gain 3200 PSTPIP1 111 15 7510578975115806 10017 gain 3279 PSTPIP1 113 15 75096101 75128723 32622 gain3200 PSTPIP1 111 15 88999998 89016848 16850 het loss 3172 114 16 68236776932753 109076 het loss 3126 RBFOX1 115 16 6823677 6932753 109076 hetloss 3126 RBFOX1 115 16 6942078 6945539 3461 gain 3173 RBFOX1 116 166942078 6945539 3461 gain 3175 RBFOX1 116 16 6942078 6945539 3461 gain3282 RBFOX1 116 16 23842653 23848772 6119 het loss 3198 PRKCB 117 1623892842 23903495 10653 gain 3199 PRKCB 118 16 23892842 23903495 10653gain 3199 PRKCB 118 16 23893969 23908248 14279 gain 3205 PRKCB 119 1623893969 23908248 14279 gain 3205 PRKCB 119 16 69044235 69050151 5916gain 3174 FUK 120 16 69044235 69050151 5916 gain 3185 FUK 120 1669052450 69081640 29190 het loss 3197 COG4 121 FUK 16 70653499 7066544711948 gain 3143 HPR 122 16 70653499 70665447 11948 gain 3152 HPR 122 1670653499 70665447 11948 gain 3192 HPR 122 16 70653499 70665447 11948gain 3200 HPR 122 16 70653499 70665447 11948 gain 3282 HPR 122 1670653499 70665447 11948 gain 3284 HPR 122 17 69341925 70202523 860598gain 3183 BTBD17 123 C17orf77 CD300A CD300C CD300E CD300LB CD300LDCD300LF DNAI2 GPR142 GPRC5C KIF19 MGC16275 RAB37 RPL38 TTYH2 17 7560815175615433 7282 het loss 3144 TBC1D16 124 17 75608151 75615433 7282 hetloss 3152 TBC1D16 124 17 75608151 75615433 7282 het loss 3163 TBC1D16124 17 75608151 75611602 3451 het loss 3192 TBC1D16 125 17 7560815175615433 7282 het loss 3200 TBC1D16 124 17 75608151 75611602 3451 hetloss 3204 TBC1D16 125 17 75608151 75611602 3451 het loss 3284 TBC1D16125 17 75608151 75611602 3451 hom loss 3009 TBC1D16 125 17 7561160275615433 3831 hom loss 3175 TBC1D16 126 17 75608151 75615433 7282 hetloss 3144 TBC1D16 124 17 75608151 75615433 7282 het loss 3152 TBC1D16124 17 75608151 75615433 7282 het loss 3163 TBC1D16 124 17 7560815175615433 7282 het loss 3200 TBC1D16 124 17 76241510 76267844 26334 gain3205 RPTOR 127 17 76247305 76265683 18378 gain 3127 RPTOR 128 1776241510 76267844 26334 gain 3205 RPTOR 127 17 76241510 76267844 26334gain 3205 RPTOR 127 18 9985530 10125331 139801 gain 3175 129 18 1276409512781985 17890 gain 3191 PTPN2 130 18 27026203 27029351 3148 het loss3125 131 18 27026203 27029351 3148 het loss 3143 131 18 2702620327029351 3148 het loss 3175 131 18 42537949 42663605 125656 gain 3125PIAS2 132 ST8SIA5 18 46917195 46945018 27823 het loss 3161 133 1859457622 59465699 8077 het loss 3145 SERPINB4 134 19 3270755 329114420389 gain 3205 135 19 46386511 46388364 1853 hom loss 3175 136 1952496536 52501292 4756 gain 3124 137 19 55247874 55252420 4546 het loss3163 FLJ26850 138 19 55247874 55252420 4546 het loss 3173 FLJ26850 13819 55247874 55252420 4546 het loss 3192 FLJ26850 138 19 5524787455252420 4546 het loss 3200 FLJ26850 138 19 55247874 55252420 4546 hetloss 3280 FLJ26850 138 19 55247874 55252420 4546 het loss 3163 FLJ26850138 19 55247874 55252420 4546 het loss 3173 FLJ26850 138 19 5524787455252420 4546 het loss 3192 FLJ26850 138 19 55250187 55252420 2233 hetloss 3194 FLJ26850 139 19 55247874 55252420 4546 het loss 3200 FLJ26850138 19 55247874 55252420 4546 het loss 3280 FLJ26850 138 19 5525018755252420 2233 hom loss 3175 FLJ26850 139 19 55250187 55252420 2233 homloss 3202 FLJ26850 139 19 56964168 57308449 344281 gain 3155 FPR2 140FPR3 ZNF350 ZNF432 ZNF577 ZNF613 ZNF614 ZNF615 ZNF649 ZNF841 19 5696416857308449 344281 gain 3157 FPR2 140 FPR3 ZNF350 ZNF432 ZNF577 ZNF613ZNF614 ZNF615 ZNF649 ZNF841 19 59013780 59023850 10070 het loss 3117NLRP12 141 19 59249279 59251831 2552 hom loss 3160 VSTM1 142 19 5924927959251831 2552 hom loss 3164 VSTM1 142 19 59250742 59251831 1089 hom loss3117 VSTM1 143 19 59249279 59251831 2552 hom loss 3160 VSTM1 142 1959249279 59251831 2552 hom loss 3164 VSTM1 142 19 59250742 59251831 1089hom loss 3277 VSTM1 143 20 17844577 17954650 110073 gain 3166 MGME1 144OVOL2 SNORD17 SNX5 20 42706680 42711434 4754 het loss 3125 ADA 145 2115234620 15312960 78340 gain 3009 NRIP1 146 21 29643302 29647950 4648het loss 3202 BACH1 147 21 44634707 44666832 32125 gain 3200 TRPM2 14821 44634707 44641658 6951 gain 3205 TRPM2 149 21 44634707 44671482 36775gain 3279 TRPM2 150 21 44637544 44669596 32052 gain 3127 TRPM2 151 2144637544 44657372 19828 gain 3185 TRPM2 152 21 44634707 44666832 32125gain 3200 TRPM2 148 21 44634707 44641658 6951 gain 3205 TRPM2 149 2144634707 44671482 36775 gain 3279 TRPM2 150 21 44637544 44669596 32052gain 3127 TRPM2 151 21 44637544 44657372 19828 gain 3185 TRPM2 152 2144634707 44666832 32125 gain 3200 TRPM2 148 21 44634707 44671482 36775gain 3279 TRPM2 150 21 44643974 44657372 13398 het loss 3161 TRPM2 15321 44637544 44669596 32052 gain 3127 TRPM2 151 21 44637544 4465737219828 gain 3185 TRPM2 152 21 44634707 44666832 32125 gain 3200 TRPM2 14821 44643974 44657372 13398 gain 3205 TRPM2 153 21 44634707 4467148236775 gain 3279 TRPM2 150 21 44637544 44669596 32052 gain 3127 TRPM2 15121 44634707 44666832 32125 gain 3200 TRPM2 148 21 44634707 4467148236775 gain 3279 TRPM2 150 21 44637544 44669596 32052 gain 3127 TRPM2 15121 44634707 44666832 32125 gain 3200 TRPM2 148 21 44660199 4468119420995 gain 3205 TRPM2 154 21 44634707 44671482 36775 gain 3279 TRPM2 15021 44637544 44669596 32052 gain 3127 TRPM2 151 21 44660199 4468119420995 gain 3205 TRPM2 154 21 44634707 44671482 36775 gain 3279 TRPM2 15021 44660199 44681194 20995 gain 3205 TRPM2 154 21 44634707 4467148236775 gain 3279 TRPM2 150 21 44660199 44681194 20995 gain 3205 TRPM2 15421 45348895 45354820 5925 het loss 3179 ADARB1 155 22 37689058 3771538526327 gain 3169 APOBEC3A 156 APOBEC3A B APOBEC3B 22 39257585 392616214036 het loss 3005 MKL1 157 22 40642402 40655210 12808 gain 3205TNFRSF13C 158 22 40655820 40673250 17430 gain 3185 159 22 4065582040675788 19968 gain 3205 160 22 40659633 40671866 12233 gain 3127 161 2240655820 40673250 17430 gain 3185 159 22 40655820 40675788 19968 gain3205 160 22 40659633 40671866 12233 gain 3127 CENPM 161 22 4065582040673250 17430 gain 3185 CENPM 159 22 40663050 40668079 5029 gain 3190CENPM 162 22 40663050 40668079 5029 gain 3202 CENPM 162 22 4065582040675788 19968 gain 3205 CENPM 160 22 40659633 40671866 12233 gain 3127CENPM 161 22 40655820 40673250 17430 gain 3185 CENPM 159 22 4065582040675788 19968 gain 3205 CENPM 160 22 40655820 40673250 17430 gain 3185CENPM 159 22 40655820 40675788 19968 gain 3205 CENPM 160 22 4065582040675788 19968 gain 3205 160 23 232907 244684 11777 het loss 3007PPP2R3B 163 23 7585301 7830994 245693 gain 3172 164 23 7585301 7830994245693 gain 3172 VCX 164 23 7769323 7779354 10031 het loss 3132 165 236465033 8093113 1628080 het loss 3171 166 23 7769323 7779354 10031 hetloss 3204 165 23 7585301 7830994 245693 gain 3172 164 23 7585301 7830994245693 gain 3172 164 23 6465033 8093113 1628080 het loss 3171 MIR651 166PNPLA4 23 7585301 7830994 245693 gain 3172 PNPLA4 164 23 4835864648408854 50208 het loss 3009 167 23 64710574 64725828 15254 gain 3125168 23 73083877 73086192 2315 hom loss 3193 JPX 169 23 73083877 730861922315 hom loss 3200 JPX 169 23 122337025 122340879 3854 hom loss 3125GRIA3 170 23 148452844 148461889 9045 het loss 3163 171 23 148452844148461889 9045 het loss 3205 171 23 148452844 148461889 9045 hom loss3144 171 23 148452844 148461889 9045 hom loss 3193 171 23 149901706149904265 2559 gain 3117 HMGB3 172 23 149901706 149904265 2559 gain 3118HMGB3 172

Table 1 lists all CNVs of interest, obtained as described in the text,with the exception that, for each entry, the original CNV start and stoppositions are noted, along with original CNV size, type (heterozygousloss, homozygous loss or gain), Case ID and gene annotation (for theCNV-subregion NOT original CNV). The final column contains SEQ IDnumbers. Standard chromosomal numbering used by those skilled in the artis used in Table 1 for the autosomal chromosomes (1-22) but, forconvenience with analysis methods, chromosome X is designated aschromosome 23 herein. All coordinates are based on hg18.

TABLE 2 CNV-subregions of interest in this study CNV CNV CNV CNV PMLRefSeq Subregion Subregion Subregion Subregion CNV Case Gene Exon NVEPML No Chr Start Stop Size Type ID Symbol overlap cases cases FET OR(SRN) 1 1086119 1135772 49653 het loss 3009 MIR200A Y 0 1 0.00511596539.43 1 MIR200B MIR429 TNFRSF18 TTLL10 1 9634094 9635206 1112 hom loss3009 PIK3CD Y 0 1 0.005115965 39.43 2 1 12018512 12032581 14069 gain3205 N 0 1 0.005115965 39.43 3 1 19593401 19602807 9406 het loss 3203CAPZB N 0 1 0.005115965 39.43 4 1 21698753 21700243 1490 het loss 3161 N0 1 0.005115965 39.43 5 1 24364786 24391166 26380 gain 3199 IFNLR1 Y 0 10.005115965 39.43 6 1 28666669 28737671 71002 gain 3161 PHACTR4 Y 0 10.005115965 39.43 7 RCC1 SNHG3 1 49372054 49380088 8034 het loss 3145AGBL4 N 0 1 0.005115965 39.43 8 1 153816159 153827698 11539 het loss3168 N 0 1 0.005115965 39.43 9 1 205607255 205610341 3086 gain 3007 N 01 0.005115965 39.43 10 1 215760485 215762451 1966 het loss 3117 GPATCH2N 0 1 0.005115965 39.43 11 1 215866737 215869900 3163 het loss 3151GPATCH2 N 0 1 0.005115965 39.43 12 2 10352668 10356083 3415 het loss3007 N 0 1 0.005115965 39.43 13 2 24457024 24462631 5607 hom loss 3204 N0 1 0.005115965 39.43 14 2 38468717 38471950 3233 het loss 3175 N 0 10.005115965 39.43 15 2 38516138 38524237 8099 het loss 3151 N 0 10.005115965 39.43 16 2 38726517 38731845 5328 het loss 3159 N 00.005115965 39.43 17 2 40620890 40624089 3199 het loss 3202 N 0 10.005115965 39.43 18 2 46631006 46643501 12495 gain 3145 RHOQ N 0 I0.005115965 39.43 19 2 55764753 55771586 6833 gain 3143 PNPT1 Y 1 30.001318303 40.7 20 2 55764753 55771586 6833 gain 3193 PNPT1 Y 1 30.001318303 40.7 21 2 55764753 55771586 6833 gain 3282 PNPT1 Y 1 30.001318303 40.7 22 2 55771587 55772965 1378 gain 3143 PNPT1 N 2 30.003126725 20.33 23 2 55771587 55772965 1378 gain 3193 PNPT1 N 2 30.003126725 20.33 24 2 55771587 55772965 1378 gain 3282 PNPT1 N 2 30.003126725 20.33 25 2 55772966 55790559 17593 gain 3143 PNPT1 Y 1 30.001318303 40.7 26 2 55772966 55790559 17593 gain 3193 PNPT1 Y 1 30.001318303 40.7 27 2 55772966 55790559 17593 gain 3282 PNPT1 Y 1 30.001318303 40.7 28 2 71190677 71191310 633 het loss 3175 MCEE Y 0 10.005115965 39.43 29 2 71191311 71198107 6796 het loss 3175 MCEE N 1 20.014314826 26.77 30 2 71191311 71198107 6796 het loss 3204 MCEE N 1 20.014314826 26.77 31 2 71198108 71200120 2012 het loss 3143 MCEE N 2 53.02E−05 34.83 32 2 71198108 71200120 2012 het loss 3175 MCEE N 2 53.02E−05 34.83 33 2 71198108 71200120 2012 het loss 13193 MCEE N 2 53.02E−05 34.83 34 2 71198108 71200120 2012 het loss 3200 MCEE N 2 53.02E−05 34.83 35 2 71198108 71200120 2012 het loss 3204 MCEE N 2 53.02E−05 34.83 36 2 74827730 74913493 85763 gain 3118 HK2 Y 0 10.005115965 39.43 37 2 105418748 105435274 16526 het loss 3193 FHL2 Y 01 0.005115965 39.43 38 2 110182348 110210249 27901 gain 3174 MALL Y 2 10.198831257 6.6 39 MIR4267 MIR4436B1 MIR4436B2 2 127823042 1278284105368 het loss 3273 N 0 1 0.005115965 39.43 40 2 134911636 134914254 2618het loss 3273 MGAT5 N 0 1 0.005115965 39.43 41 2 203005216 20301993314717 het loss 3009 BMPR2 N 2 2 0.02731135 13.37 42 2 203005216203019933 14717 het loss 3192 BMPR2 N 2 2 0.02731135 13.37 43 2203005216 203019933 14717 hom loss 3152 BMPR2 N 0 1 0.005115965 39.43 442 230212897 230216339 3442 het loss 3154 DNER N 0 1 0.005115965 39.43 453 122979920 122994402 14482 gain 3202 IQCB1 Y 0 1 0.005115965 39.43 46 426565071 26566345 1274 het loss 3010 STIM2 N 85 5 0.671895631 0.75 47 426565071 26566345 1274 het loss 3125 STIM2 N 85 5 0.671895631 0.75 48 426565071 26566345 1274 het loss 3168 STIM2 N 85 5 0.671895631 0.75 49 426565071 26566345 1274 het loss 3282 STIM2 N 85 5 0.671895631 0.75 50 426565071 26566345 1274 het loss 3284 STIM2 N 85 5 0.671895631 0.75 51 426565071 26566345 1274 hom loss 3273 STIM2 N 1 1 0.13732578 13.21 52 454838623 54873909 35286 gain 3153 PDGFRA Y 0 1 0.005115965 39.43 53 490791460 90843887 52427 gain 3168 N 0 1 0.005115965 39.43 54 4 9080086390808258 7395 het loss 3009 N 0 2 0.005115965 66.59 55 4 9080086390808258 7395 het loss 3284 N 0 2 0.005115965 66.59 56 5 4533127845785151 453873 gain 3157 HCN1 Y 0 1 0.005115965 39.43 57 5 4977121949774457 3238 gain 3273 EMB Y 0 1 0.005115965 39.43 58 5 6661941566636116 16701 gain 3010 N 0 1 0.005115965 39.43 59 5 78480194 7849729617102 gain 3205 N 0 1 0.005115965 39.43 60 5 78497296 78500551 3255 gain3132 N 0 2 0.005115965 66.59 61 5 78497296 78500551 3255 gain 3185 N 0 20.005115965 66.59 62 5 78500552 78521408 20856 gain 3132 N 0 3 2.49E−0594.48 63 5 78500552 78521408 20856 gain 3185 N 0 3 2.49E−05 94.48 64 578500552 78521408 20856 gain 3205 N 0 3 2.49E−05 94.48 65 5 7852140978526637 5228 gain 3132 N 0 2 0.005115965 66.59 66 5 78521409 785266375228 gain 3205 N 0 2 0.005115965 66.59 67 5 78526638 78531091 4453 gain3132 N 0 1 0.005115965 39.43 68 5 83490494 83495169 4675 het loss 3204EDIL3 N 0 1 0.005115965 39.43 69 5 133372071 133379727 7656 hom loss3153 N 0 1 0.005115965 39.43 70 5 137836466 137843309 6843 hom loss 3279N 1 1 0.13732578 13.21 71 5 150159466 150161037 1571 het loss 3117 N 154 0.040487703 3.62 72 5 150159466 150161037 1571 het loss 3180 N 15 40.040487703 3.62 73 5 150159466 150161037 1571 het loss 3199 N 15 40.040487703 3.62 74 5 150159466 150161037 1571 het loss 3278 N 15 40.040487703 3.62 75 5 150161038 150181399 20361 het loss 3117 N 14 40.033744017 3.88 76 5 150161038 150181399 20361 het loss 3180 N 14 40.033744017 3.88 77 5 150161038 150181399 20361 het loss 3199 N 14 40.033744017 3.88 78 5 150161038 150181399 20361 het loss 3278 N 14 40.033744017 3.88 79 5 150181400 150185189 3789 het loss 3117 N 13 40.027710312 4.18 80 5 150181400 150185189 3789 het loss 3180 N 13 40.027710312 4.18 81 5 150181400 150185189 3789 het loss 3199 N 13 40.027710312 4.18 82 5 150181400 150185189 3789 het loss 3278 N 13 40.027710312 4.18 83 5 150185190 150191626 6436 hom loss 3009 N 6 78.59E−06 16.65 84 5 150185190 150191626 6436 hom loss 3143 N 6 78.59E−06 16.65 85 5 150185190 150191626 6436 hom loss 3152 N 6 78.59E−06 16.65 86 5 150185190 150191626 6436 hom loss 3154 N 6 78.59E−06 16.65 87 5 150185190 150191626 6436 hom loss 3193 N 6 78.59E−06 16.65 88 5 150185190 150191626 6436 hom loss 3196 N 6 78.59E−06 16.65 89 5 150185190 150191626 6436 hom loss 3281 N 6 78.59E−06 16.65 90 5 150191627 150201145 9518 hom loss 3009 N 6 78.59E−06 16.65 91 5 150191627 150201145 9518 hom loss 3143 N 6 78.59E−06 16.65 92 5 150191627 150201145 9518 hom loss |3152 N 6 78.59E−06 16.65 93 5 150191627 150201145 9518 hom loss 3154 N 6 78.59E−06 16.65 94 5 150191627 150201145 9518 hom loss 3193 N 6 78.59E−06 16.65 95 5 150191627 150201145 9518 hom loss 3196 N 6 78.59E−06 16.65 96 5 150191627 150201145 9518 hom loss 3281 N 6 78.59E−06 16.65 97 5 150201146 150202601 1455 hom loss 3152 N 1 30.001318303 40.7 98 5 150201146 150202601 1455 hom loss 3154 N 1 30.001318303 40.7 99 5 150201146 150202601 1455 hom loss 3193 N 1 30.001318303 40.7 100 5 150202602 150204134 1532 het loss 3132 N 51 80.062987683 2.17 101 5 150202602 150204134 1532 het loss 3180 N 51 80.062987683 2.17 102 5 150202602 150204134 1532 het loss 3196 N 51 80.062987683 2.17 103 5 150202602 150204134 1532 het loss 3273 N 51 80.062987683 2.17 104 5 150202602 150204134 1532 het loss 3277 N 51 80.062987683 2.17 105 5 150202602 150204134 1532 het loss 3278 N 51 80.062987683 2.17 106 5 150202602 150204134 1532 het loss 3280 N 51 80.062987683 2.17 107 5 150202602 150204134 1532 het loss 3282 N 51 80.062987683 2.17 108 5 179590681 179626660 35979 het loss 3172 MAPK9 Y 01 0.005115965 39.43 109 6 2882577 2947403 64826 het loss 3196DKFZP686115217 Y 0 1 0.005115965 39.43 110 NQO2 SERPINB6 6 29646462966011 1365 het loss 3193 HTATSF1P2 Y 0 1 0.005115965 39.43 111 NQO2 651766024 51773250 7226 het loss 3167 PKHD1 N 0 1 0.005115965 39.43 112 651952217 51953475 1258 gain 3127 PKHD1 N 0 1 0.005115965 39.43 113 651953476 51965723 12247 gain 3127 PKHD1 N 0 2 0.005115965 66.59 114 651953476 51965723 12247 gain 3205 PKHD1 N 0 2 0.005115965 66.59 115 651965724 51969378 3654 gain 3127 PKHD1 N 0 1 0.005115965 39.43 116 674396294 74398409 2115 het loss 3009 SLC17A5 N 0 2 0.005115965 66.59 1176 74396294 74398409 2115 het loss 3160 SLC17A5 N 0 2 0.005115965 66.59118 6 74398410 74404837 6427 het loss 3009 SLC17A5 Y 0 1 0.00511596539.43 119 6 86416979 86431527 14548 het loss 3197 N 0 1 0.00511596539.43 120 6 91131823 91135670 3847 het loss 3171 N 0 1 0.005115965 39.43121 6 107882367 107890605 8238 het loss 3201 PDSS2 Y 0 1 0.00511596539.43 122 6 166418511 166422386 3875 het loss 3125 N 11 10 3.49E−0713.49 123 6 166418511 166422386 3875 het loss 3163 N 11 10 3.49E−0713.49 124 6 166418511 166422386 3875 het loss 3192 N 11 10 3.49E−0713.49 125 6 166418511 166422386 3875 het loss 3193 N 11 10 3.49E−0713.49 126 6 166418511 166422386 3875 het loss 3194 N 11 10 3.49E−0713.49 127 6 166418511 166422386 3875 het loss 3200 N 11 10 3.49E−0713.49 128 6 166418511 166422386 3875 het loss 3205 N 11 10 3.49E−0713.49 129 6 166418511 166422386 3875 het loss 3280 N 11 10 3.49E−0713.49 130 6 166418511 166422386 3875 het loss 3281 N 11 10 3.49E−0713.49 131 6 166418511 166422386 3875 het loss 3284 N 11 10 3.49E−0713.49 132 6 166418511 166422386 3875 hom loss 3009 N 0 3 2.49E−05 94.48133 6 166418511 166422386 3875 hom loss 3152 N 0 3 2.49E−05 94.48 134 6166418511 166422386 3875 hom loss 3175 N 0 3 2.49E−05 94.48 135 765741238 65768682 27444 gain 3152 KCTD7 Y 0 2 0.005115965 66.59 136 765741238 65768682 27444 gain 3202 KCTD7 Y 0 2 0.005115965 66.59 137 7157174966 157177843 2877 het loss 3009 PTPRN2 N 0 1 0.005115965 39.43138 7 157425841 157496238 70397 gain 3189 PTPRN2 N 1 1 0.13732578 13.21139 7 158000082 158007892 7810 het loss 3279 PTPRN2 N 1 1 0.1373257813.21 140 7 158007893 158010672 2779 het loss 3279 PTPRN2 N 5 10.358539546 2.63 141 7 158010673 158024569 13896 het loss 3279 MIR595 Y1 1 0.13732578 13.21 142 PTPRN2 8 23103186 23125443 22257 het loss 3140TNFRSF10A Y 0 1 0.005115965 39.43 143 8 39914488 39919594 5106 het loss3126 IDO2 N 0 1 0.005115965 39.43 144 8 79905654 79910286 4632 het loss3159 N 0 1 0.005115965 39.43 145 8 99790200 99799839 9639 het loss 3006STK3 N 0 1 0.005115965 39.43 146 8 102049360 102064431 15071 het loss3173 N 0 3 2.49E−05 94.48 147 8 102049360 102064431 15071 het loss 3175N 0 3 2.49E−05 94.48 148 8 102049360 102064431 15071 het loss 3282 N 0 32.49E−05 94.48 149 9 571398 580721 9323 het loss 3006 KANK1 N 2 10.198831257 6.6 150 9 580722 584647 3925 het loss 3006 KANK1 N 3 30.005933668 13.54 151 9 580722 584647 3925 het loss 3200 KANK1 N 3 30.005933668 13.54 152 9 580722 584647 3925 het loss 3282 KANK1 N 3 30.005933668 13.54 153 9 584648 598488 13840 het loss 3200 KANK1 N 2 20.02731135 13.37 154 9 584648 598488 13840 het loss 3282 KANK1 N 2 20.02731135 13.37 155 9 634039 637589 3550 het loss 3273 KANK1 N 0 20.005115965 66.59 156 9 634039 637589 3550 het loss 3282 KANK1 N 0 20.005115965 66.59 157 9 74050088 74059447 9359 het loss 3165 GDA Y 0 10.005115965 39.43 158 9 93140394 93447826 307432 gain 3198 AUH Y 0 10.005115965 39.43 159 MIR3163 MIR3910-1 MIR3910-2 NFIL3 9 118564159118575633 11474 gain 3193 ASTN2 N 0 1 0.005115965 39.43 160 9 118657526118664593 7067 het loss |3144 ASTN2 N 0 1 0.005115965 39.43 161 9119220847 119233078 12231 gain 3005 N 0 1 0.005115965 39.43 162 10899657 1071401 171744 gain 3161 GTPBP4 Y 0 1 0.005115965 39.43 163 IDI2IDI2-AS1 LARP4B 10 76217585 76411591 194006 gain 3179 KAT6B Y 0 10.005115965 39.43 164 10 116000069 116004388 4319 gain 3010 VWA2 Y 0 10.005115965 39.43 165 11 14677012 14689025 12013 het loss 3199 PDE3B N 01 0.005115965 39.43 166 11 34608313 34615878 7565 het loss 3117 EHF Y 01 0.005115965 39.43 167 11 62382087 62398462 16375 het loss 3205 SLC3A2Y 0 1 0.005115965 39.43 168 11 76631014 76643625 12611 het loss 3193GDPD4 Y 0 1 0.005115965 39.43 169 12 11616557 12114030 497473 het loss3126 ETV6 Y 0 1 0.005115965 39.43 170 12 12438904 12778142 339238 hetloss 3126 APOLD1 Y 0 1 0.005115965 39.43 171 CDKN1B CREBL2 DUSP16 GPR19LOH12CR1 12 12968705 12971310 2605 gain 3127 XXXXX N 0 1 0.00511596539.43 172 12 91845527 92201342 355815 het loss 3126 EEA1 Y 0 10.005115965 39.43 173 LOC643339 12 92215898 92567120 351222 het loss3126 LOC643339 Y 0 1 0.005115965 39.43 174 MRPL42 NUDT4 NUDT4P1 SOCS2SOCS2-AS1 UBE2N 12 92568362 93307172 738810 het loss 3126 CCDC41 Y 0 10.005115965 39.43 175 CRADD PLXNC1 12 111061085 111064486 3401 het loss3004 TRAFD1 Y 0 1 0.005115965 39.43 176 13 40939924 41026908 86984 gain3140 RGCC Y 0 1 0.005115965 39.43 177 13 75006025 75016304 10279 gain3009 COMMD6 Y 0 2 0.005115965 66.59 178 13 75006025 75016304 10279 gain3152 COMMD6 Y 0 2 0.005115965 66.59 179 13 91811087 91814369 3282 hetloss 3143 GPC5 N 1 1 0.13732578 13.21 180 13 91811087 91811118 31 homloss 3173 GPC5 N 0 1 0.005115965 39.43 181 13 110754499 110778301 23802gain 3006 ARHGEF7 Y 0 1 0.005115965 39.43 182 TEX29 14 20021118 2005546934351 gain 3205 RNASE10 Y 0 1 0.005115965 39.43 183 14 20426824 2048185255028 hom loss 3200 ECRP Y 0 1 0.005115965 39.43 184 RNASE3 14 2043081020458350 27540 het loss 3192 ECRP Y 3 1 0.256004559 4.39 185 14 2045835120481852 23501 het loss 3192 N 4 1 0.309147091 3.29 186 14 2048185320490129 8276 het loss 3192 N 1 1 0.13732578 13.21 187 14 2109668921105611 8922 het loss 3125 N 0 5 1.16E−07 152.56 188 14 2109668921105611 8922 het loss 3175 N 0 5 1.16E−07 152.56 189 14 2109668921105611 8922 het loss 3194 N 0 5 1.16E−07 152.56 190 14 2109668921105611 8922 het loss 3204 N 0 5 1.16E−07 152.56 191 14 2109668921105611 8922 het loss 3273 N 0 5 1.16E−07 152.56 192 14 2112075021125513 4763 gain 3143 N 1 2 0.014314826 26.77 193 14 21120750 211255134763 gain 3173 N 1 2 0.014314826 26.77 194 14 60901636 60909492 7856 hetloss 3193 PRKCH N 0 1 0.005115965 39.43 195 14 60912874 60921269 8395het loss 3174 PRKCH N 0 1 0.005115965 39.43 196 14 63937192 639444597267 gain 3205 MTHFD1 Y 0 1 0.005115965 39.43 197 14 95754535 957590564521 het loss 3009 BDKRB2 N 0 3 2.49E−05 94.48 198 14 95754535 957590564521 het loss 3173 BDKRB2 N 0 3 2.49E−05 94.48 199 14 95754535 957590564521 het loss 3202 BDKRB2 N 0 3 2.49E−05 94.48 200 15 66065925 6608241816493 het loss 3010 N 0 1 0.005115965 39.43 201 15 70432627 7044301710390 gain 3169 HEXA Y 0 1 0.005115965 39.43 202 15 75096101 751015235422 gain 3200 PSTPIP1 Y 0 1 0.005115965 39.43 203 15 75101524 751057884264 gain 3132 PSTPIP1 Y 0 2 0.005115965 66.59 204 15 75101524 751057884264 gain 3200 PSTPIP1 Y 0 2 0.005115965 66.59 205 15 75105789 751090863297 gain 3127 PSTPIP1 Y 0 5 1.16E−07 152.56 206 15 75105789 751090863297 gain 3132 PSTPIP1 Y 0 5 1.16E−07 152.56 207 15 75105789 751090863297 gain 3199 PSTPIP1 Y 0 5 1.16E−07 152.56 208 15 75105789 751090863297 gain 3200 PSTPIP1 Y 0 5 1.16E−07 152.56 209 15 75105789 751090863297 gain 3279 PSTPIP1 Y 0 5 1.16E−07 152.56 210 15 75109087 751158066719 gain 3127 PSTPIP1 Y 1 5 9.14E−06 69.72 211 15 75109087 751158066719 gain 3132 PSTPIP1 Y 1 5 9.14E−06 69.72 212 15 75109087 751158066719 gain 3199 PSTPIP1 Y 1 5 9.14E−06 69.72 213 15 75109087 751158066719 gain 3200 PSTPIP1 Y 1 5 9.14E−06 69.72 214 15 75109087 751158066719 gain 3279 PSTPIP1 Y 1 5 9.14E−06 69.72 215 15 75115807 751177981991 gain 3200 PSTPIP1 Y 1 1 0.13732578 13.21 216 15 88999998 8901684816850 het loss 3172 N 0 1 0.005115965 39.43 217 16 6823677 6884976 61299het loss 3126 RBFOX1 N 0 1 0.005115965 39.43 218 16 6886815 6896330 9515het loss 3126 RBFOX1 N 0 1 0.005115965 39.43 219 16 6942078 6945539 3461gain 3173 RBFOX1 N 1 3 0.001318303 40.7 220 16 6942078 6945539 3461 gain3175 RBFOX1 N 1 3 0.001318303 40.7 221 16 6942078 6945539 3461 gain 3282RBFOX1 N 1 3 0.001318303 40.7 222 16 23844022 23848772 4750 het loss3198 PRKCB N 7 1 0.447101793 1.88 223 16 23892842 23893968 1126 gain3199 PRKCB N 0 1 0.005115965 39.43 224 16 23893969 23903495 9526 gain3199 PRKCB N 0 2 0.005115965 66.59 225 16 23893969 23903495 9526 gain3205 PRKCB N 0 2 0.005115965 66.59 226 16 23903496 23908248 4752 gain3205 PRKCB Y 0 1 0.005115965 39.43 227 16 69047888 69050151 2263 gain3174 FUK N 0 2 0.005115965 66.59 228 16 69047888 69050151 2263 gain 3185FUK N 0 2 0.005115965 66.59 229 16 69052450 69081640 29190 het loss 3197COG4 Y 0 1 0.005115965 39.43 230 FUK 16 70653499 70665447 11948 gain3143 HPR Y 0 6 1.16E−07 182.82 231 16 70653499 70665447 11948 gain 3152HPR Y 0 6 1.16E−07 182.82 232 16 70653499 70665447 11948 gain 3192 HPR Y0 6 1.16E−07 182.82 233 16 70653499 70665447 11948 gain 3200 HPR Y 0 61.16E−07 182.82 234 16 70653499 70665447 11948 gain 3282 HPR Y 0 61.16E−07 182.82 235 16 70653499 70665447 11948 gain 3284 HPR Y 0 61.16E−07 182.82 236 17 69341925 70202523 860598 gain 3183 BTBD17 Y 1 10.13732578 13.21 237 C17orf77 CD300A CD300C CD300E CD300LB CD300LDCD300LF DNAI2 GPR142 GPRC5C KIF19 MGC16275 RAB37 RPL38 TTYH2 17 7560815175611602 3451 het loss 3144 TBC1D16 N 1 7 5.37E−08 100.4 238 17 7560815175611602 3451 het loss 3152 TBC1D16 N 1 7 5.37E−08 100.4 239 17 7560815175611602 3451 het loss 3163 TBC1D16 N 1 7 5.37E−08 100.4 240 17 7560815175611602 3451 het loss 3192 TBC1D16 N 1 7 5.37E−08 100.4 241 17 7560815175611602 3451 het loss 3200 TBC1D16 N 1 7 5.37E−08 100.4 242 17 7560815175611602 3451 het loss 3204 TBC1D16 N 1 7 5.37E−08 100.4 243 17 7560815175611602 3451 het loss 3284 TBC1D16 N 1 7 5.37E−08 100.4 244 17 7560815175611602 3451 hom loss 3009 TBC1D16 N 0 1 0.005115965 39.43 245 1775611602 75615433 3831 hom loss 3175 TBC1D16 N 0 1 0.005115965 39.43 24617 75611603 75615433 3830 het loss 3144 TBC1D16 N 1 4 0.000112689 55.01247 17 75611603 75615433 3830 het loss 3152 TBC1D16 N 1 4 0.00011268955.01 248 17 75611603 75615433 3830 het loss 3163 TBC1D16 N 1 40.000112689 55.01 249 17 75611603 75615433 3830 het loss 3200 TBC1D16 N1 4 0.000112689 55.01 250 17 76241510 76247304 5794 gain 3205 RPTOR N 01 0.005115965 39.43 251 17 76247305 76265683 18378 gain 3127 RPTOR N 0 20.005115965 66.59 252 17 76247305 76265683 18378 gain 3205 RPTOR N 0 20.005115965 66.59 253 17 76265684 76267844 2160 gain 3205 RPTOR N 0 10.005115965 39.43 254 18 9985530 10125331 139801 gain 3175 N 0 10.005115965 39.43 255 18 12764095 12781985 17890 gain 3191 PTPN2 Y 0 10.005115965 39.43 256 18 27026203 27029351 3148 het loss 3125 N 0 32.49E−05 94.48 257 18 27026203 27029351 3148 het loss 3143 N 0 32.49E−05 94.48 258 18 27026203 27029351 3148 het loss 3175 N 0 32.49E−05 94.48 259 18 42537949 42663605 125656 gain 3125 PIAS2 Y 0 10.005115965 39.43 260 ST8SIA5 18 46917195 46945018 27823 het loss 3161 N0 1 0.005115965 39.43 261 18 59457622 59465699 8077 het loss 3145SERPINB4 Y 0 1 0.005115965 39.43 262 19 3270755 3291144 20389 gain 3205N 0 1 0.005115965 39.43 263 19 46386511 46388364 1853 hom loss 3175 N 01 0.005115965 39.43 264 19 52496536 52501292 4756 gain 3124 N 0 10.005115965 39.43 265 19 55247874 55250186 2312 het loss 3163 FLJ26850 N4 5 0.000161709 17.38 266 19 55247874 55250186 2312 het loss 3173FLJ26850 N 4 5 0.000161709 17.38 267 19 55247874 55250186 2312 het loss3192 FLJ26850 N 4 5 0.000161709 17.38 268 19 55247874 55250186 2312 hetloss 3200 FLJ26850 N 4 5 0.000161709 17.38 269 19 55247874 55250186 2312het loss 3280 FLJ26850 N 4 5 0.000161709 17.38 270 19 55250187 552524202233 het loss 3163 FLJ26850 N 4 6 1.80E−05 21.15 271 19 5525018755252420 2233 het loss 3173 FLJ26850 N 4 6 1.80E−05 21.15 272 1955250187 55252420 2233 het loss 3192 FLJ26850 N 4 6 1.80E−05 21.15 27319 55250187 55252420 2233 het loss 3194 FLJ26850 N 4 6 1.80E−05 21.15274 19 55250187 55252420 2233 het loss 3200 FLJ26850 N 4 6 1.80E−0521.15 275 19 55250187 55252420 2233 het loss 3280 FLJ26850 N 4 61.80E−05 21.15 276 19 55250187 55252420 2233 hom loss 3175 FLJ26850 N 02 0.005115965 66.59 277 19 55250187 55252420 2233 hom loss 3202 FLJ26850N 0 2 0.005115965 66.59 278 19 56964168 57308449 344281 gain 3155 FPR2 Y3 2 0.043434433 8.91 279 FPR3 ZNF350 ZNF432 ZNF577 ZNF613 ZNF614 ZNF615ZNF649 ZNF841 19 56964168 57308449 344281 gain 3157 FPR2 Y 3 20.043434433 8.91 280 FPR3 ZNF350 ZNF432 ZNF577 ZNF613 ZNF614 ZNF615ZNF649 ZNF841 19 59016855 59023850 6995 het loss 3117 NLRP12 Y 0 10.005115965 39.43 281 19 59249279 59250741 1462 hom loss 3160 VSTM1 N 372 1 0.7 282 19 59249279 59250741 1462 hom loss 3164 VSTM1 N 37 2 1 0.7283 19 59250742 59251831 1089 hom loss 3117 VSTM1 N 38 4 0.5338383991.39 284 19 59250742 59251831 1089 hom loss 3160 VSTM1 N 38 40.533838399 1.39 285 19 59250742 59251831 1089 hom loss 3164 VSTM1 N 384 0.533838399 1.39 286 19 59250742 59251831 1089 hom loss 3277 VSTM1 N38 4 0.533838399 1.39 287 20 17844577 17954650 110073 gain 3166 MGME1 Y0 1 0.005115965 39.43 288 OVOL2 SNORD17 SNX5 20 42706680 42711434 4754het loss 3125 ADA N 0 1 0.005115965 39.43 289 21 15237071 15312960 75889gain 3009 NRIP1 Y 0 1 0.005115965 39.43 290 21 29643302 29647950 4648het loss 3202 BACH1 Y 0 1 0.005115965 39.43 291 21 44634707 446375432836 gain 3200 TRPM2 Y 1 3 0.001318303 40.7 292 21 44634707 446375432836 gain 3205 TRPM2 Y 1 3 0.001318303 40.7 293 21 44634707 446375432836 gain 3279 TRPM2 Y 1 3 0.001318303 40.7 294 21 44637544 446416584114 gain 3127 TRPM2 Y 1 5 9.14E−06 69.72 295 21 44637544 44641658 4114gain 3185 TRPM2 Y 1 5 9.14E−06 69.72 296 21 44637544 44641658 4114 gain3200 TRPM2 Y 1 5 9.14E−06 69.72 297 21 44637544 44641658 4114 gain 3205TRPM2 Y 1 5 9.14E−06 69.72 298 21 44637544 44641658 4114 gain 3279 TRPM2Y 1 5 9.14E−06 69.72 299 21 44641659 44643973 2314 gain 3127 TRPM2 Y 1 40.000112689 55.01 300 21 44641659 44643973 2314 gain 3185 TRPM2 Y 1 40.000112689 55.01 301 21 44641659 44643973 2314 gain 3200 TRPM2 Y 1 40.000112689 55.01 302 21 44641659 44643973 2314 gain 3279 TRPM2 Y 1 40.000112689 55.01 303 21 44643974 44657372 13398 het loss 3161 TRPM2 Y 11 0.13732578 13.21 304 21 44643975 44657372 13397 gain 3127 TRPM2 Y 0 51.16E−07 152.56 305 21 44643975 44657372 13397 gain 3185 TRPM2 Y 0 51.16E−07 152.56 306 21 44643975 44657372 13397 gain 3200 TRPM2 Y 0 51.16E−07 152.56 307 21 44643975 44657372 13397 gain 3205 TRPM2 Y 0 51.16E−07 152.56 308 21 44643975 44657372 13397 gain 3279 TRPM2 Y 0 51.16E−07 152.56 309 21 44657373 44660198 2825 gain 3127 TRPM2 Y 0 32.49E−05 94.48 310 21 44657373 44660198 2825 gain 3200 TRPM2 Y 0 32.49E−05 94.48 311 21 44657373 44660198 2825 gain 3279 TRPM2 Y 0 32.49E−05 94.48 312 21 44660199 44666832 6633 gain 3127 TRPM2 Y 0 42.49E−05 123.12 313 21 44660199 44666832 6633 gain 3200 TRPM2 Y 0 42.49E−05 123.12 314 21 44660199 44666832 6633 gain 3205 TRPM2 Y 0 42.49E−05 123.12 315 21 44660199 44666832 6633 gain 3279 TRPM2 Y 0 42.49E−05 123.12 316 21 44666833 44669596 2763 gain 3127 TRPM2 Y 0 32.49E−05 94.48 317 21 44666833 44669596 2763 gain 3205 TRPM2 Y 0 32.49E−05 94.48 318 21 44666833 44669596 2763 gain 3279 TRPM2 Y 0 32.49E−05 94.48 319 21 44669597 44671482 1885 gain 3205 TRPM2 Y 0 20.005115965 66.59 320 21 44669597 44671482 1885 gain 3279 TRPM2 Y 0 20.005115965 66.59 321 21 44671483 44681194 9711 gain 3205 TRPM2 Y 0 10.005115965 39.43 322 21 45348895 45354820 5925 het loss 3179 ADARB1 N 01 0.005115965 39.43 323 22 37689058 37715385 26327 gain 3169 APOBEC3A Y0 1 0.005115965 39.43 324 APOBEC3A B APOBEC3B 22 39257585 39261621 4036het loss 3005 MKL1 N 0 1 0.005115965 39.43 325 22 40642402 4065521012808 gain 3205 TNFRSF13C Y 0 1 0.005115965 39.43 326 22 4065582040659632 3812 gain 3185 N 0 2 0.005115965 66.59 327 22 40655820 406596323812 gain 3205 N 0 2 0.005115965 66.59 328 22 40659633 40663049 3416gain 3127 N 0 3 2.49E−05 94.48 329 22 40659633 40663049 3416 gain 3185 N0 3 2.49E−05 94.48 330 22 40659633 40663049 3416 gain 3205 N 0 32.49E−05 94.48 331 22 40663050 40668079 5029 gain 3127 CENPM Y 0 51.16E−07 152.56 332 22 40663050 40668079 5029 gain 3185 CENPM Y 0 51.16E−07 152.56 333 22 40663050 40668079 5029 gain 3190 CENPM Y 0 51.16E−07 152.56 334 22 40663050 40668079 5029 gain 3202 CENPM Y 0 51.16E−07 152.56 335 22 40663050 40668079 5029 gain 3205 CENPM Y 0 51.16E−07 152.56 336 22 40668080 40671866 3786 gain 3127 CENPM Y 0 32.49E−05 94.48 337 22 40668080 40671866 3786 gain 3185 CENPM Y 0 32.49E−05 94.48 338 22 40668080 40671866 3786 gain 3205 CENPM Y 0 32.49E−05 94.48 339 22 40671867 40673250 1383 gain 3185 CENPM Y 0 20.005115965 66.59 340 22 40671867 40673250 1383 gain 3205 CENPM Y 0 20.005115965 66.59 341 22 40673251 40675788 2537 gain 3205 N 0 10.005115965 39.43 342 23 232907 234429 1522 het loss 3007 PPP2R3B N 0 10.005115965 39.43 343 23 7585301 7769322 184021 gain 3172 N 5 10.358539546 2.63 344 23 7769323 7773949 4626 gain 13172 VCX Y 7 10.447101793 1.88 345 23 7773982 7779354 5372 het loss 3132 N 0 32.49E−05 94.48 346 23 7773982 7779354 5372 het loss 3171 N 0 3 2.49E−0594.48 347 23 7773982 7779354 5372 het loss 3204 N 0 3 2.49E−05 94.48 34823 7773982 7779353 5371 gain 3172 N 5 1 0.358539546 2.63 349 23 77793547815400 36046 gain 3172 N 6 1 0.404443314 2.19 350 23 7779355 8093113313758 het loss 3171 MIR651 Y 0 1 0.005115965 39.43 351 PNPLA4 237815401 7830994 15593 gain 3172 PNPLA4 Y 7 1 0.447101793 1.88 352 2348358646 48408854 50208 het loss 3009 N 0 1 0.005115965 39.43 353 2364710574 64725828 15254 gain 3125 N 0 1 0.005115965 39.43 354 2373083877 73086192 2315 hom loss 3193 JPX N 1 2 0.014314826 26.7 355 2373083877 73086192 2315 hom loss 3200 JPX N 1 2 0.014314826 26.7 356 23122337025 122340879 3854 hom loss 3125 GRIA3 N 0 1 0.005115965 39.43 35723 148452844 148461889 9045 het loss 3163 N 7 2 0.129983268 3.8 358 23148452844 148461889 9045 het loss 3205 N 7 2 0.129983268 3.8 359 23148459108 148461889 2781 hom loss 3144 N 0 2 0.005115965 66.59 360 23148459108 148461889 2781 hom loss 3193 N 0 2 0.005115965 66.59 361 23149901706 149902701 995 gain 3117 HMGB3 Y 0 2 0.005115965 66.59 362 23149901706 149902701 995 gain 3118 HMGB3 Y 0 2 0.005115965 66.59 363

Table 2 is identical to Table 1, with a number of exceptions. Firstly,the CNV coordinates listed refer to the actual CNV-subregions found tobe unique or significantly different between the disease and normalcohorts, as opposed to Table 1, which lists the original CNVs. Secondly,an extra column details whether genic CNV-subregions of interest overlapan exon or not. Third and fourth, 2 extra columns detail the number ofnormal cases and the number of disease cases that harbor the relevantCNV-subregion. Finally, 2 columns report Fisher's 2-tailed Exact Test(FET) and the odds ratio (OR). Standard chromosomal numbering used bythose skilled in the art is used in Table 2 for the autosomalchromosomes (1-22) but, for convenience with analysis methods,chromosome X is designated as chromosome 23 herein. All coordinates arein hg18.

TABLE 3 A non-redundant list of genes listed in Table 2 RefSeq NCBI GeneGene Exon Gene Gene # Symbol overlap ID Description RefSeq Summary (GN)ADARB1 intronic 104 double- This gene encodes the enzyme responsible forpre-mRNA 2 stranded RNA-s editing of the glutamate receptor subunit B bysite-specific pecific editase 1 deamination of adenosines. Studies inrat found that this isoform 1 enzyme acted on its own pre-mRNA moleculesto convert an AA dinucleotide to an AI dinucleotide which resulted in anew splice site. Alternative splicing of this gene results in severaltranscript variants, some of which have been characterized by thepresence or absence of an ALU cassette insert and a short or longC-terminal region. [provided by RefSeq, July 2008]. Transcript Variant:This variant (1), also known as ADAR2a-L1 or DRADA2a, lacks the ALUcassette insert and contains the long C-terminal region, as compared tovariant 2. The resulting isoform (1), also known as hRED1- Short, lacksan internal segment, compared to isoform 2. Publication Note: ThisRefSeq record includes a subset of the publications that are availablefor this gene. Please see the Gene record to access additionalpublications. ##RefSeq- Attributes-START## undergoes RNA editing ::PMID: 11717408, 12045112 ##RefSeq-Attributes-END## Transcript exoncombination :: AB194370.1, U76420.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025084, ERS025085 [ECO:0000348]AGBL4 intronic 84871 cytosolic N/A 3 carboxypeptidase 6 APOBEC3A exonic200315 DNA dC- This gene is a member of the cytidine deaminase genefamily. 4 >dU-editing It is one of seven related genes or pseudogenesfound in a enzyme APOBEC-3A cluster, thought to result from geneduplication, on isoform a chromosome 22. Members of the cluster encodeproteins that are structurally and functionally related to the C to URNA- editing cytidine deaminase APOBEC1. The protein encoded by thisgene lacks the zinc binding activity of other family members. Theprotein plays a role in immunity, by restricting transmission of foreignDNA such as viruses. One mechanism of foreign DNA restriction isdeamination of foreign double- stranded DNA cytidines to uridines, whichleads to DNA degradation. However, other mechanisms are also thought tobe involved, as anti-viral effect is not dependent on deaminaseactivity. Two transcript variants encoding different isoforms have beenfound for this gene. [provided by RefSeq, July 2012]. TranscriptVariant: This variant (1) represents the longer transcript and encodesthe longer isoform (a). Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: U03891.2, BC126416.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025081, ERS025084 [ECO:0000348]APOBEC3A B intronic 100913187 probable DNA This gene is a member of thecytidine deaminase gene family. 5 dC->dU- It is one of seven relatedgenes or pseudogenes found in a editing enzyme cluster, thought toresult from gene duplication, on APOBEC-3A chromosome 22. Members of thecluster encode proteins that are structurally and functionally relatedto the C to U RNA- editing cytidine deaminase APOBEC1. The proteinencoded by this gene lacks the zinc binding activity of other familymembers. The protein plays a role in immunity, by restrictingtransmission of foreign DNA such as viruses. One mechanism of foreignDNA restriction is deamination of foreign double- stranded DNA cytidinesto uridines, which leads to DNA degradation. However, other mechanismsare also thought to be involved, as anti-viral effect is not dependenton deaminase activity. The protein encoded by this gene is the same asthat encoded by APOBEC3A; however, this gene is a hybrid gene thatresults from the deletion of approximately 29.5 kb of sequence betweenthe APOBEC3A gene and the adjacent gene APOBEC3B. The breakpoints of thedeletion are within the two genes, so the deletion hybrid is predictedto have the promoter and coding region of APOBEC3A, but the 3' UTR ofAPOBEC3B. [provided by RefSeq, July 2012]. Publication Note: This RefSeqrecord includes a subset of the publications that are available for thisgene. Please see the Gene record to access additional publications.RNAseq introns :: single sample supports all introns ERS025081,ERS025084 [ECO:0000348] APOBEC3B exonic 9582 DNA dC->dU- This gene is amember of the cytidine deaminase gene family. 6 editing enzyme It is oneof seven related genes or pseudogenes found in a APOBEC-3B cluster,thought to result from gene duplication, on isoform a chromosome 22.Members of the cluster encode proteins that are structurally andfunctionally related to the C to U RNA- editing cytidine deaminaseAPOBEC1. It is thought that the proteins may be RNA editing enzymes andhave roles in growth or cell cycle control. A hybrid gene results fromthe deletion of approximately 29.5 kb of sequence between this gene,APOBEC3B, and the adjacent gene APOBEC3A. The breakpoints of thedeletion are within the two genes, so the deletion allele is predictedto have the promoter and coding region of APOBEC3A, but the 3' UTR ofAPOBEC3B. Two transcript variants encoding different isoforms have beenfound for this gene. [provided by RefSeq, July 2012]. TranscriptVariant: This variant (1) represents the longer transcript and encodesthe longer isoform (a). Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: AY743217.1 [ECO:0000332] RNAseq introns :: mixed/partialsample support ERS025081, ERS025082 [ECO:0000350] APOLD1 exonic 81575apolipoprotein L APOLD1 is an endothelial cell early response proteinthat 7 domain-containing may play a role in regulation of endothelialcell signaling and protein 1 vascular function (Regard et al., 2004[PubMed isoform 1 15102925]).[supplied by OMIM, December 2008].Transcript Variant: This variant (1) represents the longer transcriptand encodes the longer isoform (1). Sequence Note: This RefSeq recordwas created from transcript and genomic sequence data to make thesequence consistent with the reference genome assembly. The extent ofthis transcript is supported by transcript alignments. Transcript exoncombination :: BC042478.1, DR000985.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025086 [ECO:0000348] ARHGEF7exonic 8874 rho guanine Rho GTPases play a fundamental role in numerouscellular 8 nucleotide processes triggered by extracellular stimuli thatwork through exchange G protein coupled receptors. The encoded proteinbelongs to al factor 7 family of cytoplasmic proteins that activate theRas-like isoform a family of Rho proteins by exchanging bound GDP forGTP. It forms a complex with the small GTP binding protein Rac1 andrecruits Rac1 to membrane ruffles and to focal adhesions. This proteincan induce membrane ruffling. Multiple alternatively spliced transcriptvariants encoding different isoforms have been described for this gene.[provided by RefSeq, July 2008]. Transcript Variant: This variant (1)differs in the 5' UTR, 3' UTR, coding region, and uses a downstreamstart codon, compared to variant 3. Both variants 1 and 5 encode isoforma, which has a shorter N-terminus and a longer and distinct C-terminus,compared to isoform c. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: D63476.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025082 [ECO:0000348] ASTN2 intronic23245 astrotactin-2 This gene encodes a protein that is expressed in thebrain and 9 isoform a may function in neuronal migration, based onfunctional precursor studies of the related astrotactin 1 gene in humanand mouse. A deletion at this locus has been associated withschizophrenia. Multiple transcript variants encoding different proteinshave been found for this locus. [provided by RefSeq, May 2010].Transcript Variant: This variant (1) represents the longest transcriptand encodes the longest isoform (a). Transcript exon combination ::BC146756.1, AB014534.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025082 [ECO:0000348 AUH exonic 549methylglutaconyl- The methylglutaconyl-CoA hydratase, mitochondrialprotein 10 CoA hydratase, binds to the AU-rich element (ARE), a commonelement mitochondrial found in the 3' UTR of rapidly decaying mRNA suchas c-fos, precursor c-myc and granulocyte/ macrophage colony stimulatingfactor. ARE elements are involved in directing RNA to rapid degradationand deadenylation. AUH is also homologous to enol-CoA hydratase, anenzyme involved in fatty acid degradation, and has been shown to haveintrinsic hydratase enzymatic activity. AUH is thus a bifunctionalchimera between RNA binding and metabolic enzyme activity. A possiblesubcellular localization in the mitochondria has been demonstrated forthe mouse homolog of this protein which shares 92% identity with thehuman protein. It has been suggested that AUH may have a novel role as amitochondrial located AU-binding protein. Human AUH is expressed as asingle mRNA species of 1.8 kb, and translated as a 40-kDa precursorprotein which is subsequently processed to a 32- kDa mature form.[provided by RefSeq, May 2010]. Publication Note: This RefSeq recordincludes a subset of the publications that are available for this gene.Please see the Gene record to access additional publications. ##RefSeq-Attributes-START## gene product(s) localized to mito. :: reported byMitoCarta ##RefSeq-Attributes-END## Transcript exon combination ::X79888.1, AL533438.3 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025084, ERS025088 [ECO:0000348] BACH1 exonic 571BTB Domain This gene encodes a transcription factor that belongs to the11 And CNC cap'n'collar type of basic region leucine zipper factorfamily Homolog 1 (CNC-bZip). The encoded protein contains broad complex,tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) domains, whichis atypical of CNC-bZip family members. These BTB/POZ domains facilitateprotein-protein interactions and formation of homo- and/orhetero-oligomers. When this encoded protein forms a heterodimer withMafK, it functions as a repressor of Maf recognition element (MARE) andtranscription is repressed. Multiple alternatively spliced transcriptvariants have been identified for this gene. [provided by RefSeq, May2009]. Transcript Variant: This variant (3), also named BACH1t, differsin the 5' UTR, 3' coding region and 3' UTR (compared to variant 1). Thisvariant is represented as non-coding because the use of the 5'- mostsupported translational start codon, as used in variant 1, renders thetranscript a candidate for nonsense-mediated mRNA decay (NMD). Thistranscript represents the splice variant reported by Kanezaki et al.(PMID: 11069897). Publication Note: This RefSeq record includes a subsetof the publications that are available for this gene. Please see theGene record to access additional publications. RNAseq introns ::mixed/partial sample support ERS025084, ERS025088 [ECO:0000350] BDKRB2intronic 624 B2 bradykinin This gene encodes a receptor for bradykinin.The 9 aa 12 receptor bradykinin peptide elicits many responses includingvasodilation, edema, smooth muscle spasm and pain fiber stimulation.This receptor associates with G proteins that stimulate aphosphatidylinositol-calcium second messenger system. Alternate startcodons result in two isoforms of the protein. [provided by RefSeq. July2008]. Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::DC369062.1, DC417219.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025090 [ECO:0000348] BMPR2 intronic 659 boneThis gene encodes a member of the bone morphogenetic 13 morphogeneticprotein (BMP) receptor family of transmembrane protein receptorserine/threonine kinases. The ligands of this receptor are type-2precursor BMPs, which are members of the TGF-beta superfamily. BMPs areinvolved in endochondral bone formation and embryogenesis. Theseproteins transduce their signals through the formation of heteromericcomplexes of two different types of serine (threonine) kinase receptors:type I receptors of about 50-55 kD and type II receptors of about 70-80kD. Type II receptors bind ligands in the absence of type I receptors,but they require their respective type I receptors for signaling,whereas type I receptors require their respective type II receptors forligand binding. Mutations in this gene have been associated with primarypulmonary hypertension, both familial and fenfluramine-associated, andwith pulmonary venoocclusive disease. [provided by RefSeq, July 2008].Sequence Note: This RefSeq record was created from transcript andgenomic sequence data to make the sequence consistent with the referencegenome assembly. The extent of this transcript is supported bytranscript alignments. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: BC052985.2, AK292430.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025081, ERS025082 [ECO:0000348]BTBD17 exonic 388419 BTB/POZ N/A 14 domain- containing protein 17precursor C17orf77 exonic 146723 uncharacterized N/A 15 protein C17orf77precursor CAPZB intronic 832 F-actin-capping This gene encodes the betasubunit of the barbed-end actin 16 protein subunit binding protein,which belongs to the F-actin capping protein beta isoform 1 family. Thecapping protein is a heterodimeric actin capping protein that blocksactin filament assembly and disassembly at the fast growing (barbed)filament ends and functions in regulating actin filament dynamics aswell as in stabilizing actin filament lengths in muscle and nonmusclecells. A pseudogene of this gene is located on the long arm ofchromosome 2. Multiple alternatively spliced transcript variantsencoding different isoforms have been found.[provided by RefSeq, August2013]. Transcript Variant: This variant (1) encodes isoform 1.Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::BC107752.1, BM451686.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025088 [ECO:0000348] CCDC41 exonic 51134centrosomal N/A 17 protein of 83 kDa CD300A exonic 11314 CMRF35-likeThis gene encodes a member of the CD300 glycoprotein 18 molecule 8family of cell surface proteins found on leukocytes involved isoform 1in immune response signaling pathways. This gene is located precursor onchromosome 17 in a cluster with all but one of the other family members.Multiple transcript variants encoding different isoforms have been foundfor this gene. [provided by RefSeq, February 2012]. Transcript Variant:This variant (1) represents the longer transcript and encodes the longerprotein (isoform 1), also referred to as IRC1a. Publication Note: ThisRefSeq record includes a subset of the publications that are availablefor this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: BC032352.1, AL531420.3[ECO:0000332] RNAseq introns :: single sample supports all intronsERS025081, ERS025083 [ECO:0000348 CD300C exonic 10871 CMRF35-like TheCMRF35 antigen, which was identified by reactivity with 19 molecule 6 amonoclonal antibody, is present on monocytes, neutrophils, precursor andsome T and B lymphocytes (Jackson et al., 1992 [PubMed 1349532]).[supplied by OMIM, Mar 2008]. Transcript exon combination :: BC022279.1,BM922826.1 [ECO:0000332] RNAseq introns :: single sample supports allintrons ERS025084, ERS025087 [ECO:0000348] CD300E exonic 342510CMRF35-like This gene encodes a member of the CD300 glycoprotein 20molecule 2 family of cell surface proteins expressed on myeloid cells.precursor The protein interacts with the TYRO protein tyrosine kinase-binding protein and is thought to act as an activating receptor.[provided by RefSeq, November 2012]. Sequence Note: This RefSeq recordwas created from transcript and genomic sequence data to make thesequence consistent with the reference genome assembly. The genomiccoordinates used for the transcript record were based on transcriptalignments. An in-frame AUG is located 41 codons upstream of theannotated translation start site but is not being annotated as a startsite since it is not conserved and is in a weak Kozak sequence context.##RefSeq-Attributes-START## CDS uses downstream in-frame AUG ::downstream AUG is associated with N-terminal localization signal##RefSeq-Attributes- END## Transcript exon combination :: AK303545.1,BX648376.1 [ECO:0000332] RNAseq introns :: single sample supports allintrons ERS025084, ERS025088 [ECO:0000348] CD300LB exonic 124599CMRF35-like CD300LB is a nonclassical activating receptor of themolecule 7 immunoglobulin (1g) superfamily expressed on myeloid cellsprecursor (Martinez-Barriocanal and Sayos, 2006 [PubMed 16920917]).[supplied by OMIM, March 2008]. CCDS Note: The coding region has beenupdated to shorten the N-terminus to one that is more supported byavailable conservation data and paralogous family members. The updatehas a predicted N-terminal signal peptide, which is consistent withfunctional support for the protein (e.g., PMIDs 16920917, 19359216).Transcript exon combination :: BC028091.1, AY359025.1 [ECO:0000332]RNAseq introns :: single sample supports all introns ERS025084,ERS025088 [ECO:0000348] ##RefSeq- Attributes-START## CDS uses downstreamin-frame AUG :: downstream AUG is associated with N-terminallocalization signal ##RefSeq-Attributes-END## CD300LD exonic 1001314CMRF35-like |N/A 22 39 molecule 4 precursor CD300LF exonic 146722CMRF35-like CD300LF is an inhibitory receptor of the Ig superfamily 23molecule 1 expressed on myeloid cells. It mediates negative regulatoryprecursor signals by recruiting SHP1 (PTPN6; MIM 176883) or SHIP(INPPSD; MIM 601582) (Sui et al., 2004 [PubMed 15184070]; Alvarez-Erricoet al., 2004 [PubMed 15549731]).[supplied by OMIM, March 2008]. SequenceNote: The RefSeq transcript and protein were derived from genomicsequence to make the sequence consistent with the reference genomeassembly. The genomic coordinates used for the transcript record werebased on alignments. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: AF251706.1, AY358545.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025084 [ECO:0000348] CDKNIB exonic1027 cyclin- This gene encodes a cyclin-dependent kinase inhibitor,which 24 dependent shares a limited similarity with CDK inhibitorCDKN1A/p21. kinase The encoded protein binds to and prevents theactivation of inhibitor 1B cyclin E-CDK2 or cyclin D-CDK4 complexes, andthus controls the cell cycle progression at G1. The degradation of thisprotein, which is triggered by its CDK dependent phosphorylation andsubsequent ubiquitination by SCF complexes, is required for the cellulartransition from quiescence to the proliferative state. [provided byRefSeq, July 2008]. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: BC001971.1, AY004255.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025081, ERS025082 [ECO:0000348]CENPM exonic 79019 centromere The centromere is a specialized chromatindomain, present 25 protein M throughout the cell cycle, that acts as aplatform on which the isoform a transient assembly of the kinetochoreoccurs during mitosis. All active centromeres are characterized by thepresence of long arrays of nucleosomes in which CENPA (MIM 117139)replaces histone H3 (see MIM 601128). CENPM is an additional factorrequired for centromere assembly (Foltz et al., 2006 [PubMed16622419]).[supplied by OMIM, March 2008]. Transcript Variant: Thisvariant (1) represents the longer transcript and encodes the longerisoform (a). Publication Note: This RefSeq record includes a subset ofthe publications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::BC000705.2, BC007495.2 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025085, ERS025088 [ECO:0000348] COG4 exonic25839 conserved The protein encoded by this gene is a component of an 26oligomeric oligomeric protein complex involved in the structure andGolgi function of the Golgi apparatus. Defects in this gene may be acomplex cause of congenital disorder of glycosylation type IIj. Twosubunit 4 transcript variants encoding different isoforms have beenisoform 1 found for this gene.[provided by RefSeq, August 2010].Transcript Variant: This variant (1) represents the longer transcriptand encodes the longer isoform (1). Transcript exon combination ::BC072438.1, AK022874.1 [ECO:0000332] RNAseq introns :: mixed/partialsample support ERS025081, ERS025082 [ECO:0000350] COMMD6 exonic 170622COMM COMMD6 belongs to a family of NF-kappa-B (see RELA; 27 domain- MIM164014)-inhibiting proteins characterized by the containing presence ofa COMM domain (see COMMD1; MIM 607238) protein 6 (de Bie et al., 2006[PubMed 16573520]). [supplied by isoform a OMIM, March 2009]. Transcriptexon combination :: HY028175.1, DW440523.1 [ECO:0000332] RNAseq introns:: single sample supports all introns ERS025088 [ECO:0000348] CRADDexonic 8738 death domain- The protein encoded by this gene is a deathdomain 28 necrosis containing (CARD/DD)-containing protein and has beenshown to protein CRADD induce cell apoptosis. Through its CARD domain,this protein interacts with, and thus recruits, caspase 2/ICH1 to thecell death signal transduction complex that includes tumor necrosisfactor receptor 1 (TNFRIA), RIPK1/RIP kinase, and numbers of other CARDdomain-containing proteins [provided by RefSeq, July 2008]. PublicationNote: This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: BX480215.1, BC017042.1[ECO:0000332] RNAseq introns :: single sample supports all intronsERS025081, ERS025083 [ECO:0000348] CREBL2 exonic 1389 CAMP- CAMPresponse element (CRE)-binding protein-like-2 29 responsive (CREBL2) wasidentified in a search to find genes in a element- commonly deletedregion on chromosome 12p13 flanked by binding ETV6 and CDKN1B genes,frequently associated with protein-like 2 hematopoietic malignancies, aswell as breast, non-small-cell lung and ovarian cancers. CREBL2 shares a41% identity with CRE-binding protein (CREB) over a 48-base long regionwhich encodes the bZip domain of CREB. The bZip domain consists of about30 amino acids rich in basic residues involved in DNA binding, followedby a leucine zipper motif involved in protein dimerization. Thissuggests that CREBL2 encodes a protein with DNA binding capabilities.The occurance of CREBL2 deletion in malignancy suggests that CREBL2 mayact as a tumor suppressor gene. [provided by RefSeq, July 2008].Transcript exon combination :: BC106052.1, AF039081.1 [ECO:0000332]RNAseq introns :: single sample supports all introns ERS025081,ERS025082 [ECO:0000348] DNAI2 exonic 64446 dynein The protein encoded bythis gene belongs to the dynein 30 intermediate intermediate chainfamily, and is part of the dynein complex chain 2, of respiratory ciliaand sperm flagella. Mutations in this gene axonemal are associated withprimary ciliary dyskinesia type 9. isoform 1 Alternatively splicedtranscript variants encoding different isoforms have been noted for thisgene. [provided by RefSeq, March 2010]. Transcript Variant: This variant(1) encodes the longer isoform (1). Transcript exon combination ::AF250288.1 [ECO:0000332] RNAseq introns :: single sample supports allintrons ERS025085 [ECO:0000348] ##RefSeq- Attributes-START## NMDcandidate :: translation inferred from conservation##RefSeq-Attributes-END## DNER intronic 92737 delta and N/A 31Notch-like epidermal growth factor- related receptor precursor DUSP16exonic 80824 dual specificity This gene encodes a mitogen-activatedprotein kinase 32 protein phosphatase that is a member of the dualspecificity protein phosphatase 16 phosphatase subfamily. Thesephosphatases inactivate their target kinases by dephosphorylating boththe phosphoserine/threonine and phosphotyrosine residues. The encodedprotein specifically regulates the c-Jun amino- terminal kinase (JNK)and extracellular signal-regulated kinase (ERK) pathways. [provided byRefSeq, May 2010]. Sequence Note: This RefSeq record was created fromtranscript and genomic sequence data to make the sequence consistentwith the reference genome assembly. The genomic coordinates used for thetranscript record were based on transcript alignments. Publication Note:This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: AF506796.1, AB052156.1[ECO:0000332] RNAseq introns :: single sample supports all intronsERS025084, ERS025088 [ECO:0000348] ECRP exonic 643332 N/A N/A 33 EDIL3intronic 10085 EGF-like The protein encoded by this gene is an integrinligand. It 34 repeat and plays an important role in mediatingangiogenesis and may be discoidin I-like important in vessel wallremodeling and development. It also domain-containing influencesendothelial cell behavior. [provided by RefSeq, July protein 3 isoform 12008]. Transcript Variant: This variant (1) encodes the longer precursorisoform (1). Sequence Note: This RefSeq record was created fromtranscript and genomic sequence data to make the sequence consistentwith the reference genome assembly. The genomic coordinates used for thetranscript record were based on transcript alignments. Publication Note:This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: BC030828.1, U70312.1[ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081,ERS025082 [ECO:0000350] EEA1 exonic 8411 early endosome N/A 35 antigen 1EHF both 26298 ETS homologous This gene encodes a protein that belongsto an ETS 36 factor isoform 1 transcription factor subfamilycharacterized by epithelial- precursor specific expression (ESEs). Theencoded protein acts as a transcriptional repressor and may be involvedin epithelial differentiation and carcinogenesis. Three transcriptvariants Jencoding different isoforms have been found for this gene.[provided by RefSeq, June 2011]. Transcript Variant: This variant (1)encodes the longest isoform (1). Sequence Note: This RefSeq record wascreated from transcript and genomic sequence data to make the sequenceconsistent with the reference genome assembly. The genomic coordinatesused for the transcript record were based on transcript alignments.Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::AK310867.1 [ECO:0000332] RNAseq introns :: single sample supports allintrons ERS025084, ERS025086 [ECO:0000348] EMB exonic 133418 embiginThis gene encodes a transmembrane glycoprotein that is a 37 precursormember of the immunoglobulin superfamily. The encoded protein may beinvolved in cell growth and development by mediating interactionsbetween the cell and extracellular matrix. A pseudogene of this gene isfound on chromosome 1. [provided by RefSeq, January 2009]. Transcriptexon combination :: BC059398.1, AK300860.1 [ECO:0000332] RNAseq introns:: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] ETV6exonic 2120 transcription |rearrangements associated with leukemia andcongenital 38 factor ETV6 This gene encodes an ETS family transcriptionfactor. The product of this gene contains two functional domains: a N-terminal pointed (PNT) domain that is involved in protein- proteininteractions with itself and other proteins, and a C- terminalDNA-binding domain. Gene knockout studies in mice suggest that it isrequired for hematopoiesis and maintenance of the developing vascularnetwork. This gene is known to be involved in a large number ofchromosomal fibrosarcoma. [provided by RefSeq, September 2008].Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::BC043399.1, U11732.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025082 [ECO:0000348] FHL2 exonic 2274four and a halfs This gene encodes a member of the four-and-a-half-LIM-39 LIM domains only protein family. Family members contain two highlyprotein 2 conserved, tandemly arranged, zinc finger domains with fourhighly conserved cysteines binding a zinc atom in each zinc finger. Thisprotein is thought to have a role in the assembly of extracellularmembranes. Also, this gene is down-regulated during transformation ofnormal myoblasts to rhabdomyosarcoma cells and the encoded protein mayfunction as a link between presenilin-2 and an intracellular signalingpathway. Multiple alternatively spliced variants, encoding the sameprotein, have been identified. [provided by RefSeq, August 2011].Transcript Variant: This variant (1) differs in the 5' UTR compared tovariant 2. Variants 1, 2, 4 and 5 encode the same isoform. PublicationNote: This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. ##RefSeq-Attributes-START## CDS uses downstream in-frameAUG :: lack of evidence for use of upstream AUG##RefSeq-Attributes-END## Transcript exon combination :: BC093049.1,AL523628.3 [ECO:0000332] RNAseq introns :: single sample supports allintrons ERS025084, ERS025088 [ECO:0000348] FLJ26850 intronic 400710 N/AN/A 40 FPR2 exonic 2358 N-formyl peptide N/A 41 receptor 2 FPR3 exonic2359 N-formyl peptide N/A 42 receptor 3 FUK both 197258 L-fucose kinaseThe protein encoded by this gene belongs to the GHMP 43 (galacto-,homoserine, mevalonate and phosphomevalonate) kinase family andcatalyzes the phosphorylation of L-fucose to form beta-L-fucose1-phosphate. This enzyme catalyzes the first step in the utilization offree L-fucose in glycoprotein and glycolipid synthesis. L-fucose may beimportant in mediating a number of cell-cell interactions such as bloodgroup antigen recognition, inflammation, and metastatis. While severaltranscript variants may exist for this gene, the full-length nature ofonly one has been described to date. [provided by RefSeq, July 2008].Transcript exon combination:: AJ441184.1, BC032542.1 [ECO:0000332]RNAseq introns :: mixed/partial sample support ERS025081, ERS025082[ECO:0000350] GDA exonic 9615 guanine deaminase This gene encodes anenzyme responsible for the hydrolytic 44 isoform a deamination ofguanine. Studies in rat ortholog suggest this gene plays a role inmicrotubule assembly. Multiple transcript variants encoding differentisoforms have been found for this gene. [provided by RefSeq, November2011]. Transcript Variant: This variant (1) encodes the longest isoform(a). Sequence Note: This RefSeq record was created from transcript andgenomic sequence data to make the sequence consistent with the referencegenome assembly. The genomic coordinates used for the transcript recordwere based on transcript alignments. RNAseq introns :: mixed/partialsample support ERS025082, ERS025083 [ECO:0000350] GDPD4 exonic 220032glycerophosphodiester N/A 45 phosphodiesterase domain-containing protein4 GPATCH2 intronic 55105 G patch N/A 46 domain-containing protein 2 GPC5intronic 2262 glypican-5 Cell surface heparan sulfate proteoglycans arecomposed of a 47 precursor membrane-associated protein core substitutedwith a variable number of heparan sulfate chains. Members of theglypican- related integral membrane proteoglycan family (GRIPS) containa core protein anchored to the cytoplasmic membrane via a glycosylphosphatidylinositol linkage. These proteins may play a role in thecontrol of cell division and growth regulation. [provided by RefSeq,July 2008]. Publication Note: This RefSeq record includes a subset ofthe publications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::BC030584.1, BC039730.1 [ECO:0000332] RNAseq introns :: mixed/partialsample support ERS025082, ERS025083 [ECO:0000350] GPR19 exonic 2842probable G- N/A 48 protein coupled receptor 19 GPR142 exonic 350383probable G- GPR 142 is a member of the rhodopsin family of G protein- 49protein coupled coupled receptors (GPRs) (Fredriksson et al., 2003[PubMed receptor 142 14623098]).[supplied by OMIM, March 2008].Transcript exon combination :: AB196530.1, AY288421.1 [ECO:0000332]GPRC5C exonic 55890 G-protein The protein encoded by this gene is amember of the type 3 G 50 coupled receptor protein-coupled receptorfamily. Members of this superfamily family C group 5 are characterizedby a signature 7-transmembrane domain member C motif. The specificfunction of this protein is unknown; isoform a however, this protein maymediate the cellular effects of retinoic acid on the G protein signaltransduction cascade. Two transcript variants encoding differentisoforms have been found for this gene. [provided by RefSeq, July 2008].Transcript Variant: This variant (1) represents the longer transcriptand encodes the longer isoform (a). Transcript exon combination ::BC110848.1, AK131210.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025083 [ECO:0000348] GRIA3 intronic2892 glutamate receptor 3 Glutamate receptors are the predominantexcitatory 51 isoform 1 precursor neurotransmitter receptors in themammalian brain and are activated in a variety of normalneurophysiologic processes. These receptors are heteromeric proteincomplexes composed of multiple subunits, arranged to form ligand-gatedion channels. The classification of glutamate receptors is based ontheir activation by different pharmacologic agonists. The subunitencoded by this gene belongs to a family of AMPA(alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)- sensitiveglutamate receptors, and is subject to RNA editing (AGA->GGA; R->G).Alternative splicing at this locus results in different isoforms, whichmay vary in their signal transduction properties. [provided by RefSeq,July 2008]. Transcript Variant: This variant (1) encodes isoform 1 (alsoknown as flip isoform). RNA editing (AGA->GGA) changes Arg775Gly.Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. ##RefSeq-Attributes-START##undergoes RNA editing :: PMID: 10688364, 7992055##RefSeq-Attributes-END## Transcript exon combination :: U10301.1[ECO:0000332] RNAseq introns :: single sample supports all intronsERS025082, ERS025084 [ECO:0000348] GTPBP4 exonic 23560 nucleolar GTP-GTP-binding proteins are GTPases and function as molecular 52 bindingprotein 1 switches that can flip between two states: active, when GTP isbound, and inactive, when GDP is bound. 'Active' in this context usuallymeans that the molecule acts as a signal to trigger other events in thecell. When an extracellular ligand binds to a G-protein-linked receptor,the receptor changes its conformation and switches on the trimeric Gproteins that associate with it by causing them to eject their GDP andreplace it with GTP. The switch is turned off when the G proteinhydrolyzes its own bound GTP, converting it back to GDP. But before thatoccurs, the active protein has an opportunity to diffuse away from thereceptor and deliver its message for a prolonged period to itsdownstream target. [provided by RefSeq, July 2008]. Transcript exoncombination :: AK001552.1, AK222861.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025081, ERS025082 [ECO:0000348]HCN1 exonic 348980 potassium/sodium The membrane protein encoded by thisgene is a hyperpolarization- 53 hyperpolarization- activated cationchannel that contributes to the native pacemaker activated cycliccurrents in heart and neurons. The encoded protein can homodimerizenucleotide-gated or heterodimerize with other pore-forming subunits toform a channel 1 potassium channel. This channel may act as a receptorfor sour tastes. [provided by RefSeq, October 2011]. Sequence Note: ThisRefSeq record was created from transcript and genomic sequence data tomake the sequence consistent with the reference genome assembly. Thegenomic coordinates used for the transcript record were based ontranscript alignments. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: AF488549.1, AF064876.1 [ECO:0000332] RNAseq introns ::mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] HEXAexonic 3073 beta- This gene encodes the alpha subunit of the lysosomalenzyme 54 hexosaminidase beta-hexosaminidase that, together with thecofactor GM2 subunit activator protein, catalyzes the degradation of theganglioside alpha GM2, and other molecules containing terminal N-acetylpreproprotein hexosamines. Beta-hexosaminidase is composed of twosubunits, alpha and beta, which are encoded by separate genes. Bothbeta-hexosaminidase alpha and beta subunits are members of family 20 ofglycosyl hydrolases. Mutations in the alpha or beta subunit genes leadto an accumulation of GM2 ganglioside in neurons and neurodegenerativedisorders termed the GM2 gangliosidoses. Alpha subunit gene mutationslead to Tay-Sachs disease (GM2-gangliosidosis type I). [provided byRefSeq, July 2009]. Sequence Note: This RefSeq record was created fromtranscript and genomic sequence data because no single transcript wasavailable for the full length of the gene. The extent of this transcriptis supported by transcript alignments. Publication Note: This RefSeqrecord includes a subset of the publications that are available for thisgene. Please see the Gene record to access additional publications.Transcript exon combination :: M13520.1, CR627386.1 [ECO:0000332] RNAseqintrons :: single sample supports all introns ERS025084, ERS025088[ECO:0000348] HK2 exonic 3099 hexokinase-2 Hexokinases phosphorylateglucose to produce glucose-6- 55 phosphate, the first step in mostglucose metabolism pathways. This gene encodes hexokinase 2, thepredominant form found in skeletal muscle. It localizes to the outermembrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in theincreased rate of glycolysis seen in rapidly growing cancer cells.[provided by RefSeq, April 2009]. Publication Note: This RefSeq recordincludes a subset of the publications that are available for this gene.Please see the Gene record to access additional publications. Transcriptexon combination :: BC064369.1, AF148513.1 [ECO:0000332] RNAseq introns:: single sample supports all introns ERS025083, ERS025084 [ECO:0000348]HMGB3 exonic 3149 high mobility HMGB3 belongs to the high mobility group(HMG) protein 56 group protein superfamily. Like HMG1 (MIM 163905) andHMG2 (MIM B3 163906), HMGB3 contains DNA-binding HMG box domains and isclassified into the HMG box subfamily. Members of the HMG box subfamilyare thought to play a fundamental role in DNA replication, nucleosomeassembly and transcription (Wilke et al., 1997 [PubMed 9370291]; Nemethet al., 2006 [PubMed 16945912]). [supplied by OMIM, March 2008].Transcript exon combination :: Y10043.1, BG176733.1 [ECO:0000332] RNAseqintrons :: single sample supports all introns ERS025081, ERS025082[ECO:0000348] HPR exonic 3250 haptoglobin- This gene encodes ahaptoglobin-related protein that binds 57 related hemoglobin asefficiently as haptoglobin. Unlike haptoglobin, protein plasmaconcentration of this protein is unaffected in patients precursor withsickle cell anemia and extensive intravascular hemolysis, suggesting adifference in binding between haptoglobin- hemoglobin andhaptoglobin-related protein-hemoglobin complexes to CD163, thehemoglobin scavenger receptor. This protein may also be a clinicallyimportant predictor of recurrence of breast cancer. [provided by RefSeq,October 2011]. Publication Note: This RefSeq record includes a subset ofthe publications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::CB147217.1, CB122261.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025084, ERS025088 [ECO:0000348] HTATSF1P 2exonic 401233 N/A N/A 58 IDI2 exonic 91734 isopentenyl- N/A 59diphosphate Delta- isomerase 2 IDI2-AS1 exonic 55853 N/A N/A 60 IDO2intronic | 169355 indoleamine Along with the enzymes encoded by the INDO(MIM 0 2,3-dioxygenase 147435) and TDO2 (MIM 191070) genes, the enzymeencoded by the INDOLI gene metabolizes tryptophan in the kynureninepathway (Ball et al., 2007 [PubMed 17499941]). [supplied by OMIM,February 2011]. Sequence Note: The RefSeq transcript 3' UTR was derivedfrom genomic sequence to make the sequence consistent with the referencegenome assembly. The genomic coordinates used were based on transcriptalignments. IFNLR1 exonic 163702 interferon The protein encoded by thisgene belongs to the class II 62 lambda cytokine receptor family. Thisprotein forms a receptor receptor 1 complex with interleukine 10receptor, beta (IL10RB). The isoform 1 receptor complex has been shownto interact with three precursor closely related cytokines, includinginterleukin 28A (IL28A), interleukin 28B (IL28B), and interleukin 29(IL29). The expression of all three cytokines can be induced by viralinfection. The cells overexpressing this protein have been found to haveenhanced responses to IL28A and IL29, but decreased response to IL28B.Three alternatively spliced transcript variants encoding distinctisoforms have been reported. [provided by RefSeq, July 2008]. TranscriptVariant: This variant (1) represents the longest transcript and itencodes the longest protein (isoform 1). Publication Note: This RefSeqrecord includes a subset of the publications that are available for thisgene. Please see the Gene record to access additional publications.Transcript exon combination :: AF439325.1, AKI60364.1 [ECO:0000332]RNAseq introns :: single sample supports all introns ERS025084[ECO:0000348 IQCB1 exonic 9657 calmodulin- This gene encodes anephrocystin protein that interacts with 63 binding motif- calmodulinand the retinitis pigmentosa GTPase regulator containing protein. Theencoded protein has a central coiled-coil region protein 1 and twocalmodulin-binding IQ domains. It is localized to the isoform a primarycilia of renal epithelial cells and connecting cilia of photoreceptorcells. The protein is thought to play a role in ciliary function.Defects in this gene result in Senior-Loken syndrome type 5. Alternativesplicing results in multiple transcript variants. [provided by RefSeq,November 2009]. Transcript Variant: This variant (1) encodes the longerisoform (a). Publication Note: This RefSeq record includes a subset ofthe publications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::D25278.1, AY714228.1 [ECO:0000332] RNAseq introns :: mixed/partialsample support ERS025081, ERS025082 [ECO:0000350] JPX intronic 554203JPX is a nonprotein-coding RNA transcribed from a gene 64 within theX-inactivation center (XIC; MIM 314670) that appears to participate in Xchromosome inactivation (Tian et al., 2010 [PubMed 21029862]). [suppliedby OMIM, February 2011]. Transcript exon combination :: BC071776.1[ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081,ERS025082 [ECO:0000350] KANK1 intronic 23189 KN motif and The proteinencoded by this gene belongs to the Kank family 65 ankyrin repeat ofproteins, which contain multiple ankyrin repeat domains. domain- Thisfamily member functions in cytoskeleton formation by containingregulating actin polymerization. This gene is a candidate protein 1tumor suppressor for renal cell carcinoma. Mutations in this isoform agene cause cerebral palsy spastic quadriplegic type 2, a central nervoussystem development disorder. A t(5;9) translocation results in fusion ofthe platelet-derived growth factor receptor beta gene (PDGFRB) onchromosome 5 with this gene in a myeloproliferative neoplasm featuringsevere thrombocythemia. Alternative splicing of this gene results inmultiple transcript variants. A related pseuodgene has been identifiedon chromosome 20. [provided by RefSeq, March 2012]. Transcript Variant:This variant (1) represents the shortest transcript but encodes thelonger isoform (a, also known as Kank-L). Variants 1, 3 and 4 all encodeisoform a. Sequence Note: This RefSeq record was created from transcriptand genomic sequence data to make the sequence consistent with thereference genome assembly. The genomic coordinates used for thetranscript record were based on transcript alignments. Publication Note:This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: AL833161.1, AK292989.1[ECO:0000332] RNAseq introns :: single sample supports all intronsERS025084, ERS025085 [ECO:0000348] KAT6B exonic 23522 histone Theprotein encoded by this gene is a histone 66 acetyltransferaseacetyltransferase and component of the MOZ/MORF protein KAT6B complex.In addition to its acetyltransferase activity, the isoform 1 encodedprotein has transcriptional activation activity in its N-terminal endand transcriptional repression activity in its C- terminal end. Thisprotein is necessary for RUNX2-dependent transcriptional activation andcould be involved in brain development. Mutations have been found inpatients with genitopatellar syndrome. A translocation of this gene andthe CREBBP gene results in acute myeloid leukemias. Three transcriptvariants encoding different isoforms have been found for this gene.[provided by RefSeq, March 2012]. Transcript Variant: This variant (1)represents the longest transcript and encodes the longest isoform (1).Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::AF217500.1, BC150618.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025083, ERS025084 [ECO:0000348] KCTD7 exonic154881 BTB/POZ This gene encodes a member of the potassium channel 6'domain- tetramerization domain-containing protein family. Familycontaining members are identified on a structural basis and contain anprotein amino-terminal domain similar to the T1 domain present in KCTD7the voltage-gated potassium channel. Mutations in this gene isoform 1have been associated with progressive myoclonic epilepsy-3. Alternativesplicing results in multiple transcript variants. [provided by RefSeq,January 2011]. Transcript Variant: This variant (1) represents thelonger transcript and encodes the longer isoform (1). Sequence Note:This RefSeq record was created from transcript and genomic sequence datato make the sequence consistent with the reference genome assembly. Thegenomic coordinates used for the transcript record were based ontranscript alignments. Transcript exon combination :: AK056631.1,BU902852.1 [ECO:0000332] RNAseq introns :: single sample supports allintrons ERS025081, ERS025083 [ECO:0000348 KIF19 exonic 124602kinesin-like N/A 68 protein KIF19 LARP4B exonic 23185 Ia-related Thisgene encodes a member of an evolutionarily conserved 69 protein 4Bprotein family implicated in RNA metabolism and translation. Members ofthis family are characterized by the presence of an La motif, which isoften located adjacent to one or more RNA recognition motifs (RRM).Together, the two motifs constitute the functional region of the proteinand enable its interaction with the RNA substrate. This protein familyis divided into five sub-families: the genuine La proteins and fourLa-related protein (LARP) sub-families. The protein encoded by this genebelongs to LARP sub-family 4. It is a cytoplasmic protein that may playa stimulatory role in translation. [provided by RefSeq, October 2012].Sequence Note: This RefSeq record was created from transcript andgenomic sequence data to make the sequence consistent with the referencegenome assembly. The genomic coordinates used for the transcript recordwere based on transcript alignments. CDS exon combination :: BC152443.1,D86971.2 [ECO:0000331] RNAseq introns :: mixed/partial sample supportERS025088 [ECO:0000350] LOC643339 exonic 643339 N/A N/A 70 LOH12CRIexonic 118426 loss of N/A 71 heterozygosity 12 chromosomal region 1protein MALL exonic 7851 MAL-like This gene encodes an element of themachinery for raft- 72 protein mediated trafficking in endothelialcells. The encoded protein, a member of the MAL proteolipid family,predominantly localizes in glycolipid- and cholesterol-enriched membrane(GEM) rafts. It interacts with caveolin-1. [provided by RefSeq, July2008]. Transcript exon combination :: AK125647.1, AK056616.1[ECO:0000332] RNAseq introns : single sample supports all intronsERS025084, ERS025088 [ECO:0000348] MAPK9 exonic 5601 mitogen- Theprotein encoded by this gene is a member of the MAP 73 activated kinasefamily. MAP kinases act as an integration point for protein kinasemultiple biochemical signals, and are involved in a wide 9 isoformvariety of cellular processes such as proliferation, alpha 1differentiation, transcription regulation and development. This kinasetargets specific transcription factors, and thus mediatesimmediate-early gene expression in response to various cell stimuli. Itis most closely related to MAPK8, both of which are involved in UVradiation induced apoptosis, thought to be related to the cytochromec-mediated cell death pathway. This gene and MAPK8 are also known asc-Jun N-terminal kinases. This kinase blocks the ubiquitination of tumorsuppressor p53, and thus it increases the stability of p53 innonstressed cells. Studies of this gene's mouse counterpart suggest akey role in T-cell differentiation. Several alternatively splicedtranscript variants encoding distinct isoforms have been reported.[provided by RefSeq, September 2008]. Transcript Variant: This variant(JNK2-al) uses a different acceptor splice site in the last coding exoncompared to transcript variant JNK2-a2, resulting in a frameshift and ashorter isoform (JNK2 alphal) with a different C-terminus, compared toisoform JNK2 alpha2. The JNK2-a1 variant differs from the JNK2-b1variant in the use of an alternate internal coding exon of the samelength. Thus, JNK2 alpha1 isoform is the same length as JNK2 beta1isoform, with a few aa differences in an internal protein segment.Sequence Note: This RefSeq record was created from transcript andgenomic sequence data because no single transcript was available for thefull length of the gene. The extent of this transcript is supported bytranscript alignments. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. CDS exon combination:: U34821.1 [ECO:0000331] RNAseq introns :: mixed/partial sample supportERS025081, ERS025082 [ECO:0000350] MCEE both 84693 methylmalony Theproduct of this gene catalyzes the interconversion of D- 74 1-CoA andL-methylmalonyl-CoA during the degradation of epimerase, branched chainamino acids. odd chain-length fatty acids, and mitochondrial othermetabolites. Mutations in this gene result in precursormethylmalonyl-CoA epimerase deficiency, which is presented as mild tomoderate methylmalonic aciduria. [provided by RefSeq, Juyl 2008].Transcript exon combination :: BC020825.1, BG567074.1 [ECO:0000332]RNAseq introns :: single sample supports all introns ERS025081,ERS025082 [ECO:0000348] MGAT5 intronic 4249 alpha-1,6- The proteinencoded by this gene belongs to the glycosyltransferase 75mannosylglyco- family. It catalyzes the addition ofbeta-1,6-N-acetylglucosamine protein 6-beta-N- to the alpha-linkedmannose of biantennary N-linked acetylglucosaminyl- oligosaccharidespresent on the newly synthesized transferase A glycoproteins. It is oneof the most important enzymes involved in the regulation of thebiosynthesis of glycoprotein oligosaccharides. Alterations of theoligosaccharides on cell surface glycoproteins cause significant changesin the adhesive or migratory behavior of a cell. Increase in theactivity of this enzyme has been correlated with the progression ofinvasive malignancies. [provided by RefSeq, October 2011]. SequenceNote: This RefSeq record was created from transcript and genomicsequence data to make the sequence consistent with the reference genomeassembly. The genomic coordinates used for the transcript record werebased on transcript alignments. Publication Note: This RefSeq recordincludes a subset of the publications that are available for this gene.Please see the Gene record to access additional publications. Transcriptexon combination :: D17716.1, AF113921.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025081, ERS025082 [ECO:0000348]MGC16275 exonic 85001 N/A N/A 76 MGME1 exonic 92667 mitochondrial N/A 77genome maintenance exonuclease 1 MIR200A exonic 406983 microRNAs(miRNAs) are short (20-24 nt) non-coding RNAs 78 that are involved inpost-transcriptional regulation of gene expression in multicellularorganisms by affecting both the stability and translation of mRNAs.miRNAs are transcribed by RNA polymerase II as part of capped andpolyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by miRBase. Some sequence at theS' and 3' ends may not be included in the intermediate precursor miRNAproduced by Drosha cleavage. Publication Note: This RefSeq recordincludes a subset of the publications that are available for this gene.Please see the Gene record to access additional publications. MIR200Bexonic 406984 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 79that are involved in post-transcriptional regulation of gene expressionin multicellular organisms by affecting both the stability andtranslation of mRNAs. miRNAs are transcribed by RNA polymerase II aspart of capped and polyadenylated primary transcripts (pri-miRNAs) thatcan be either protein- coding or non-coding. The primary transcript iscleaved by the Drosha ribonuclease III enzyme to produce anapproximately 70-nt stem-loop precursor miRNA (pre- miRNA), which isfurther cleaved by the cytoplasmic Dicer ribonuclease to generate themature miRNA and antisense miRNA star (miRNA*) products. The maturemiRNA is incorporated into a RNA-induced silencing complex (RISC), whichrecognizes target mRNAs through imperfect base pairing with the miRNAand most commonly results in translational inhibition or destabilizationof the target mRNA. The RefSeq represents the predicted microRNAstem-loop. [provided by RefSeq, September 2009]. Sequence Note: Thisrecord represents a predicted microRNA stem-loop as defined by miRBase.Some sequence at the 5' and 3' ends may not be included in theintermediate precursor miRNA produced by Drosha cleavage. PublicationNote: This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. MIR429 exonic 554210 microRNAs (miRNAs) are short (20-24nt) non-coding RNAs 80 that are involved in post-transcriptionalregulation of gene expression in multicellular organisms by affectingboth the stability and translation of mRNAs. miRNAs are transcribed byRNA polymerase II as part of capped and polyadenylated primarytranscripts (pri-miRNAs) that can be either protein- coding ornon-coding. The primary transcript is cleaved by the Drosha ribonucleaseIII enzyme to produce an approximately 70-nt stem-loop precursor miRNA(pre- miRNA), which is further cleaved by the cytoplasmic Dicerribonuclease to generate the mature miRNA and antisense miRNA star(miRNA*) products. The mature miRNA is incorporated into a RNA-inducedsilencing complex (RISC), which recognizes target mRNAs throughimperfect base pairing with the miRNA and most commonly results intranslational inhibition or destabilization of the target mRNA. TheRefSeq represents the predicted microRNA stem-loop. [provided by RefSeq,September 2009]. Sequence Note: This record represents a predictedmicroRNA stem-loop as defined by miRBase. Some sequence at the 5' and 3'ends may not be included in the intermediate precursor miRNA produced byDrosha cleavage. Publication Note: This RefSeq record includes a subsetof the publications that are available for this gene. Please see theGene record to access additional publications. MIR595 exonic 693180microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 81 that areinvolved in post-transcriptional regulation of gene expression inmulticellular organisms by affecting both the stability and translationof mRNAs. miRNAs are transcribed by RNA polymerase II as part of cappedand polyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by miRBase. Some sequence at the5' and 3' ends may not be included in the intermediate precursor miRNAproduced by Drosha cleavage. MIR651 exonic 723779 microRNAs (miRNAs) areshort (20-24 nt) non-coding RNAs 82 that are involved inpost-transcriptional regulation of gene expression in multicellularorganisms by affecting both the stability and translation of mRNAs.miRNAs are transcribed by RNA polymerase II as part of capped andpolyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by miRBase. Some sequence at the5' and 3' ends may not be included in the intermediate precursor miRNAproduced by Drosha cleavage. MIR3163 exonic 100423029 microRNAs (miRNAs)are short (20-24 nt) non-coding RNAs 83 that are involved inpost-transcriptional regulation of gene expression in multicellularorganisms by affecting both the stability and translation of mRNAs.miRNAs are transcribed by RNA polymerase II as part of capped andpolyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by miRBase. Some sequence at the5' and 3' ends may not be included in the intermediate precursor miRNAproduced by Drosha cleavage. MIR3910-1 exonic 100500821 microRNAs(miRNAs) are short (20-24 nt) non-coding RNAs 84 that are involved inpost-transcriptional regulation of gene expression in multicellularorganisms by affecting both the stability and translation of mRNAs.miRNAs are transcribed by RNA polymerase II as part of capped andpolyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- (miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by miRBase. Some sequence at the5' and 3' ends may not be included in the intermediate precursor miRNAproduced by Drosha cleavage. MIR3910-2 exonic 100500902 microRNAs(miRNAs) are short (20-24 nt) non-coding RNAs 85 that are involved inpost-transcriptional regulation of gene expression in multicellularorganisms by affecting both the stability and translation of mRNAs.miRNAs are transcribed by RNA polymerase Il as part of capped andpolyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by miR Base. Some sequence atthe 5' and 3' ends may not be included in the intermediate precursormiRNA produced by Drosha cleavage. MIR4267 exonic 100422994 microRNAs(miRNAs) are short (20-24 nt) non-coding RNAs 86 that are involved inpost-transcriptional regulation of gene expression in multicellularorganisms by affecting both the stability and translation of mRNAs.miRNAs are transcribed by RNA polymerase II as part of capped andpolyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- (miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by miRBase. Some sequence at the5' and 3' ends may not be included in the intermediate precursor miRNAproduced by Drosha cleavage. MIR4436B1 exonic 100616123 microRNAs(miRNAs) are short (20-24 nt) non-coding RNAs 87 that are involved inpost-transcriptional regulation of gene expression in multicellularorganisms by affecting both the stability and translation of mRNAs.miRNAs are transcribed by RNA polymerase II as part of capped andpolyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by miRBase. Some sequence at the5' and 3' ends may not be included in the intermediate precursor miRNAproduced by Drosha cleavage. MIR4436B2 exonic 100847033 microRNAs(miRNAs) are short (20-24 nt) non-coding RNAs 88 that are involved inpost-transcriptional regulation of gene expression in multicellularorganisms by affecting both the stability and translation of mRNAs.miRNAs are transcribed by RNA polymerase II as part of capped andpolyadenylated primary transcripts (pri-miRNAs) that can be eitherprotein- coding or non-coding. The primary transcript is cleaved by theDrosha ribonuclease III enzyme to produce an approximately 70-ntstem-loop precursor miRNA (pre- miRNA), which is further cleaved by thecytoplasmic Dicer ribonuclease to generate the mature miRNA andantisense miRNA star (miRNA*) products. The mature miRNA is incorporatedinto a RNA-induced silencing complex (RISC), which recognizes targetmRNAs through imperfect base pairing with the miRNA and most commonlyresults in translational inhibition or destabilization of the targetmRNA. The RefSeq represents the predicted microRNA stem-loop. [providedby RefSeq, September 2009]. Sequence Note: This record represents apredicted microRNA stem-loop as defined by [miRBase. Some sequence atthe 5' and 3' ends may not be included in the intermediate precursormiRNA produced by Drosha cleavage. MKL1 intronic 57591 MKL/myocardin-This The protein encoded by this gene interacts with the 89 like protein1 transcription factor myocardin, a key regulator of smooth muscle celldifferentiation. The encoded protein is predominantly nuclear and mayhelp transduce signals from the cytoskeleton to the nucleus. This geneis involved in a specific translocation event that creates a fusion ofthis gene and the RNA-binding motif protein-15 gene. This translocationhas been associated with acute megakaryocytic leukemia. [provided byRefSeq, July 2008]. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: AB037859.2, AJ297258.1 [ECO:0000332] RNAseq introns ::mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] MRPL42exonic 28977 39S ribosomal Mammalian mitochondrial ribosomal proteinsare encoded by 90 protein L42, nuclear genes and help in proteinsynthesis within the mitochondrial mitochondrion. Mitochondrialribosomes (mitoribosomes) precursor consist of a small 28S subunit and alarge 39S subunit. They have an estimated 75% protein to rRNAcomposition compared to prokaryotic ribosomes, where this ratio isreversed. Another difference between mammalian mitoribosomes andprokaryotic ribosomes is that the latter contain a 5S rRNA. Amongdifferent species, the proteins comprising the mitoribosome differgreatly in sequence, and sometimes in biochemical properties, whichprevents easy recognition by sequence homology. This gene encodes aprotein identified as belonging to both the 28S and the 39S subunits.Alternative splicing results in multiple transcript variants.Pseudogenes corresponding to this gene are found on chromosomes 4q, 6p,6q, 7p, and 15q. [provided by RefSeq, May 2011]. Transcript Variant:This variant (1) encodes the supported protein. Both variants 1 and 2encode the same protein. Sequence Note: This RefSeq record was createdfrom transcript and genomic sequence data to make the sequenceconsistent with the reference genome assembly. The genomic coordinatesused for the transcript record were based on transcript alignments.##RefSeq-Attributes-START## gene product(s) localized to mito. ::reported by MitoCarta ##RefSeq-Attributes-END## Transcript exoncombination :: AK000285.1, AF151038.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025081, ERS025082 [ECO:0000348]MTHFD1 exonic 4522 C-1- This gene encodes a protein that possesses threedistinct 91 tetrahydrofolate enzymatic activities,5,10-methylenetetrahydrofolate synthase, dehydrogenase,5,10-methenyltetrahydrofolate cytoplasmic cyclohydrolase and10-formyltetrahydrofolate synthetase. Each of these activities catalyzesone of three sequential reactions in the interconversion of 1-carbonderivatives of tetrahydrofolate, which are substrates for methionine,thymidylate, and de novo purine syntheses. The trifunctional enzymaticactivities are conferred by two major domains, an aminoterminal portioncontaining the dehydrogenase and cyclohydrolase activities and a largersynthetase domain. [provided by RefSeq, July 2008]. Publication Note:This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. ##RefSeq-Attributes-START## CDS uses downstream in-frameAUG :: experimental evidence (PMID:3053686) ##RefSeq-Attributes-END##Transcript exon combination :: BC050420.1, J04031.1 [ECO:0000332] RNAseqintrons :: single sample supports all introns ERS025081, ERS025082[ECO:0000348 NFIL3 exonic 4783 nuclear factor Expression ofinterleukin-3 (IL3; MIM 147740) is restricted 92 interleukin-3- toactivated T cells, natural killer (NK) cells, and mast cell regulatedlines. Transcription initiation depends on the activating proteincapacity of specific protein factors, such as NFIL3, that bind toregulatory regions of the gene, usually upstream of the transcriptionstart site (Zhang et al., 1995 [PubMed 7565758]).[supplied by OMIM,February 2009]. Publication Note: This RefSeq record includes a subsetof the publications that are available for this gene. Please see theGene record to access additional publications. Transcript exoncombination :: S79880.1, U26173.1 [ECO:0000332] RNAseq introns :: singlesample supports all introns ERS025081, ERS025082 [ECO:0000348] NLRP12exonic 91662 NACHT, LRR This gene encodes a member of the CATERPILLERfamily 9. and PYD of cytoplasmic proteins. The encoded protein, whichcontains domains- an N-terminal pyrin domain, a NACHT domain, a NACHT-containing associated domain, and a C-terminus leucine-rich repeatprotein 12 region, functions as an attenuating factor of inflammation byisoform 2 suppressing inflammatory responses in activated monocytes.Mutations in this gene cause familial cold autoinflammatory syndrometype 2. Alternative splicing results in multiple transcript variants.[provided by RefSeq, March 2013]. Transcript Variant: This variant (2)uses an alternate splice site in the central coding region, compared tovariant 3, resulting in an isoform (2) that is 1 aa shorter than isoform3. Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::AY095146.1, BC028069.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025089 [ECO:0000348] NQO2 exonic 4835ribosyldihydro NQO2 (EC 1.10.99.2) is a flavoprotein that catalyzes the2- 94 nicotinamide electron reduction of various quinones, redox dyes,and the dehydrogenase vitamin K menadione. NQO2 predominantly uses[quinone] dihydronicotinamide riboside (NRH) as the electron donor(summary by Wu et al., 1997 [PubMed 9367528]). [supplied by OMIM, July2010]. Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::J02888.1, AK311746.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025082 [ECO:0000348} NRIP1 exonic8204 nuclear Nuclear receptor interacting protein 1 (NRIP1) is a nuclear95 receptor- protein that specifically interacts with thehormone-dependent interacting activation domain AF2 of nuclearreceptors. Also known as protein 1 RIP140, this protein modulatestranscriptional activity of the estrogen receptor. [provided by RefSeq,July 2008]. Sequence Note: The RefSeq transcript and protein werederived from transcript and genomic sequence to make the sequenceconsistent with the reference genome assembly. The extent of this RefSeqtranscript is supported by transcript alignments. Publication Note: ThisRefSeq record includes a subset of the publications that are availablefor this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: AK289786.1, DA230125.1[ECO:0000332] RNAseq introns :: single sample supports all intronsERS025098 [ECO:0000348] NUDT4 exonic 11163 diphosphoinositol The proteinencoded by this gene regulates the turnover of 96 polyphosphatediphosphoinositol polyphosphates. The turnover of these phosphohydrolasehigh-energy diphosphoinositol polyphosphates represents a 2 isoformalpha molecular switching activity with important regulatoryconsequences. Molecular switching by diphosphoinositol polyphosphatesmay contribute to regulating intracellular trafficking. Severalalternatively spliced transcript variants have been described, but thefull-length nature of some variants has not been determined. IsoformsDIPP2alpha and DIPP2beta are distinguishable from each other solely byDIPP2beta possessing one additional amino acid due to intron boundaryskidding in alternate splicing. [provided by RefSeq, July 2008].Transcript Variant: This variant (1) encodes the predominant isoform(alpha). Transcript exon combination :: AF191651.1, AF191650.1[ECO:0000332] RNAseq introns :: single sample supports all intronsERS025081, ERS025082 [ECO:0000348] NUDT4P1 exonic 440672 N/A N/A 97OVOL2 exonic 58495 transcription N/A 98 factor Ovo-like 2 PDE3B intronic5140 CGMP- N/A 99 inhibited 3',5'-cyclic phosphodiesterase B PDGFRAexonic 5156 platelet- This gene encodes a cell surface tyrosine kinasereceptor for 100 derived members of the platelet-derived growth factorfamily. These growth factor growth factors are mitogens for cells ofmesenchymal origin. receptor alpha The identity of the growth factorbound to a receptor precursor monomer determines whether the functionalreceptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studiessuggest that this gene plays a role in organ development, wound healing,and tumor progression. Mutations in this gene have been associated withidiopathic hypereosinophilic syndrome, somatic and familialgastrointestinal stromal tumors, and a variety of other cancers.[provided by RefSeq, March 2012]. Sequence Note: This RefSeq record wascreated from transcript and genomic sequence data because no singletranscript was available for the full length of the gene. The extent ofthis transcript is supported by transcript alignments and orthologousdata. Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::M21574.1, M22734.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025084 [ECO:0000348] PDSS2 exonic57107 decaprenyl- The protein encoded by this gene is an enzyme that 101diphosphate synthesizes the prenyl side-chain of coenzyme Q, or synthaseubiquinone, one of the key elements in the respiratory chain. subunit 2The gene product catalyzes the formation of all trans- polyprenylpyrophosphates from isopentyl diphosphate in the assembly ofpolyisoprenoid side chains, the first step in coenzyme Q biosynthesis.Defects in this gene are a cause of coenzyme Q10 deficiency.[provided byRefSeq, October 2009]. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: BC039906.1, AF254956.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025084, ERS025088 [ECO:0000348]PHACTR4 exonic 65979 phosphatase This gene encodes a member of thephosphatase and actin 102 and actin regulator (PHACTR) family. OtherPHACTR family regulator 4 members have been shown to inhibit proteinphosphatase 1 isoform 1 (PP1) activity, and the homolog of this gene inthe mouse has been shown to interact with actin and PP1. Multipletranscript variants encoding different isoforms have been found for thisgene. [provided by RefSeq, July 2008]. Transcript Variant: This variant(1) represents the longer transcript but encodes the shorter isoform(1). Sequence Note: This RefSeq record was created from transcript andgenomic sequence data to make the sequence consistent with the referencegenome assembly. The genomic coordinates used for the transcript recordwere based on transcript alignments. Transcript exon combination ::CR749449.1, BC029266.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025084, ERS025087 [ECO:0000348 PIAS2 exonic 9063E3 SUMO- This gene encodes a member of the protein inhibitor of 103protein ligase activated STAT (PIAS) family. PIAS proteins function asPIAS2 SUMO E3 ligases and play important roles in many cellular isoformalpha processes by mediating the sumoylation of target proteins.Alternatively spliced transcript variants encoding multiple isoformshave been observed for this gene. Isoforms of the encoded proteinenhance the sumoylation of specific target proteins including the p53tumor suppressor protein, c-Jun, and the androgen receptor. A pseudogeneof this gene is located on the short arm of chromosome 4. The symbolMIZ1 has also been associated with ZBTB17 which is a different genelocated on chromosome 1. [provided by RefSeq, August 2011]. TranscriptVariant: This variant (alpha) utilizes an alternate 3' coding exon,compared to variant beta, resulting in a shorter isoform (alpha) thathas a unique C-terminus compared to isoform beta. Sequence Note: ThisRefSeq record was created from transcript and genomic sequence data tomake the sequence consistent with the reference genome assembly. Thegenomic coordinates used for the transcript record were based ontranscript alignments. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: BC015190.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025088 [ECO:0000348] PIK3CD exonic 5293phosphatidylinositol Phosphoinositide 3-kinases (PI3Ks) phosphorylateinositol 104 4,5-bisphosphate lipids and are involved in the immuneresponse. The protein 3-kinase catalytic encoded by this gene is a classI PI3K found primarily in subunit delta leukocytes. Like other class IPI3Ks (p110-alpha p110-beta, isoform and p1 10-gamma), the encodedprotein binds p85 adapter proteins and GTP-bound RAS. However, unlikethe other class I PI3Ks, this protein phosphorylates itself, not p85protein. [provided by RefSeq, July 2010]. Publication Note: This RefSeqrecord includes a subset of the publications that are available for thisgene. Please see the Gene record to access additional publications.Transcript exon combination :: U86453.1, Y10055.2 [ECO:0000332] RNAseqintrons :: single sample supports all introns ERS025089 [ECO:0000348]PKHD1 intronic 5314 fibrocystin The protein encoded by this gene ispredicted to have a single 105 isoform 1 transmembrane (TM)-spanningdomain and multiple copies of precursor an immunoglobulin-likeplexin-transcription-factor domain. Alternative splicing results in twotranscript variants encoding different isoforms. Other alternativelyspliced transcripts have been described, but the full length sequenceshave not been determined. Several of these transcripts are predicted toencode truncated products which lack the TM and may be secreted.Mutations in this gene cause autosomal recessive polycystic kidneydisease, also known as polycystic kidney and hepatic disease-1.[provided by RefSeq, July 2008]. Transcript Variant: This variant (1)encodes the longer isoform of this protein. Publication Note: ThisRefSeq record includes a subset of the publications that are availablefor this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: AY074797.1, AF480064.1[ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025084,ERS025085 [ECO:0000350] PLXNC1 exonic 10154 Plexin CI This gene encodesa member of the plexin family. Plexins are 106 transmembrane receptorsfor semaphorins, a large family of proteins that regulate axon guidance,cell motility and migration, and the immune response. The encodedprotein and its ligand regulate melanocyte adhesion, and viralsemaphorins may modulate the immune response by binding to thisreceptor. The encoded protein may be a tumor suppressor protein formelanoma. Alternatively spliced transcript variants have been observedfor this gene. [provided by RefSeq, January 2011]. Transcript Variant:This variant (2) lacks multiple S'exons but contains an alternate 5'exon, compared to variant 1. This variant is represented as non- codingdue to the presence of an upstream ORF that is predicted to interferewith translation of the longest in-frame ORF. Translation of theupstream ORF renders the transcript a candidate for nonsense-mediatedmRNA decay (NMD). Publication Note: This RefSeq record includes a subsetof the publications that are available for this gene. Please see theGene record to access additional publications. RNAseq introns :: singlesample supports all introns ERS025084, ERS025088 [ECO:0000348] PNPLA4exonic 8228 patatin-like This gene encodes a member of the patatin-likefamily of 107 phospholipase phospholipases. The encoded enzyme has bothtriacylglycerol domain- lipase and transacylase activities and may beinvolved in containing adipocyte triglyceride homeostasis. Alternatesplicing results protein 4 in multiple transcript variants. A pseudogeneof this gene is isoform 1 found on chromosome Y. [provided by RefSeq,February 2010]. precursor Transcript Variant: This variant (1)represents the longest transcript and encodes the longer isoform (1).Variants 1 and 2 encode the same isoform (1). Sequence Note: The RefSeqtranscript and protein were derived from transcript and genomic sequenceto make the sequence consistent with the reference genome assembly. Theextent of this transcript is supported by transcript alignments.Transcript exon combination :: U03886.1, AK289888.1 [ECO:0000332] RNAseqintrons :: single sample supports all introns ERS025091, ERS025098[ECO:0000348] PNPT1 both 87178 polyribonucleotide The protein encoded bythis gene belongs to the evolutionary 108 nucleotidyltransferase 1,conserved polynucleotide phosphorylase family comprised of mitochondrialphosphate dependent 3'-to-5' exoribonucleases implicated in precursorRNA processing and degradation. This enzyme is predominantly localizedin the mitochondrial intermembrane space and is involved in import ofRNA to mitochondria. Mutations in this gene have been associated withcombined oxidative phosphorylation deficiency-13 and autosomal recessivenonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3and 7. [provided by RefSeq, December 2012]. Publication Note: ThisRefSeq record includes a subset of the publications that are availablefor this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: BC053660.1, AJ458465.1[ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081,ERS025082 [ECO:0000350] ##RefSeq- Attributes-START## gene product(s)localized to mito. :: PMID: 12798676; reported by MitoCarta ##RefSeq-Attributes-END## PPP2R3B intronic 28227 serine/threonine- Proteinphosphatase 2 (formerly named type 2A) is one of the 109 protein fourmajor Ser/Thr phosphatases and is implicated in the phosphatase negativecontrol of cell growth and division. Protein 2A regulatory phosphatase 2holoenzymes are heterotrimeric proteins subunit B″ composed of astructural subunit A, a catalytic subunit C, and subunit beta aregulatory subunit B. The regulatory subunit is encoded by a diverse setof genes that have been grouped into the B/PR55, B'/PR61, and B″/PR72families. These different regulatory subunits confer distinct enzymaticspecificities and intracellular localizations to the holozenzyme. Theproduct of this gene belongs to the B″ family. The B″ family has beenfurther divided into subfamilies. The product of this gene belongs tothe beta subfamily of regulatory subunit B″. [provided by RefSeq, April2010]. Sequence Note: This RefSeq record was created from transcript andgenomic sequence data to make the sequence consistent with the referencegenome assembly. The genomic coordinates used for the transcript recordwere based on transcript alignments. Transcript exon combination ::BK000521.1, BC063429.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025084 [ECO:0000348] PRKCB both 5579 proteinkinase Protein kinase C (PKC) is a family of serine- and threonine- 110C beta type specific protein kinases that can be activated by calciumand isoform 1 second messenger diacylglycerol. PKC family membersphosphorylate a wide variety of protein targets and are known to beinvolved in diverse cellular signaling pathways. PKC family members alsoserve as major receptors for phorbol esters, a class of tumor promoters.Each member of the PKC family has a specific expression profile and isbelieved to play a distinct role in cells. The protein encoded by thisgene is one of the PKC family members. This protein kinase has beenreported to be involved in many different cellular functions, such as Bcell activation, apoptosis induction, endothelial cell proliferation,and intestinal sugar absorption. Studies in mice also suggest that thiskinase may also regulate neuronal functions and correlate fear-inducedconflict behavior after stress. Alternatively spliced transcriptvariants encoding distinct isoforms have been reported. [provided byRefSeq, July 2008]. Transcript Variant: This variant (1) uses analternate splice junction at the 5' end of the last exon compared tovariant 2. The resulting isoform (1) has a distinct and shorterC-terminus compared to isoform 2. Sequence Note: This RefSeq record wascreated from transcript and genomic sequence data because no singletranscript was available for the full length of the gene. The extent ofthis transcript is supported by transcript alignments. Publication Note:This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: [X06318.1 [ECO:0000332]RNAseq introns :: single sample supports all introns ERS025082,ERS025084 [ECO:0000348] PRKCH intronic 5583 protein kinase Proteinkinase C (PKC) is a family of serine- and threonine- 111 C beta typespecific protein kinases that can be activated by calcium and isoformthe second messenger diacylglycerol. PKC family members phosphorylate awide variety of protein targets and are known to be involved in diversecellular signaling pathways. PKC family members also serve as majorreceptors for phorbol esters, a class of tumor promoters. Each member ofthe PKC family has a specific expression profile and is believed to playa distinct role in cells. The protein encoded by this gene is one of thePKC family members. It is a calcium-independent andphospholipids-dependent protein kinase. It is predominantly expressed inepithelial tissues and has been shown to reside specifically in the cellnucleus. This protein kinase can regulate keratinocyte differentiationby activating the MAP kinase MAPK13 (p38delta)-activated protein kinasecascade that targets CCAAT/enhancer-binding protein alpha (CEBPA). It isalso found to mediate the transcription activation of thetransglutaminase 1 (TGM1) gene. [provided by RefSeq, July 2008].Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::BC037268.1, AK290183.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025083 [ECO:0000348] PSTPIP1 exonic9051 proline-serine- The protein encoded by this gene binds to thecytoplasmic tail 112 threonine of CD2, an effector of T cell activationand adhesion, phosphatase- negatively affecting CD2-triggered T cellactivation. The interacting encoded protein appears to be a scaffoldprotein and a protein 1 regulator of the actin cytoskeleton. It has alsobeen shown to bind ABL1, PTPN18, WAS, CD2AP, and PTPN12. Mutations inthis gene are a cause of PAPA syndrome. [provided by RefSeq, July 2008].Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::BC008602.1, U94778.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025084, ERS025088 [ECO:0000348] PTPN2 exonic5771 tyrosine- The protein encoded by this gene is a member of theprotein 113 protein tyrosine phosphatase (PTP) family. Members of thePTP phosphatase family share a highly conserved catalytic motif, whichis non-receptor essential for the catalytic activity. PTPs are known tobe type 2 signaling molecules that regulate a variety of cellularisoform 1 processes including cell growth, differentiation, mitoticcycle, and oncogenic transformation. Epidermal growth factor receptorand the adaptor protein Shc were reported to be substrates of this PTP,which suggested the roles in growth factor mediated cell signaling.Multiple alternatively spliced transcript variants encoding differentisoforms have been found. Two highly related but distinctly processedpseudogenes that localize to chromosomes 1 and 13, respectively, havebeen reported. [provided by RefSeq, May 2011]. Transcript Variant: Thisvariant (1) encodes the longest isoform (1). Publication Note: ThisRefSeq record includes a subset of the publications that are availablefor this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: M25393.1, AK292570.1[ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081,ERS025082 [ECO:0000350] PTPRN2 intronic 5799 receptor-type The proteinencoded by this gene is a member of the protein 114 tyrosine- tyrosinephosphatase (PTP) family. PTPs are known to be protein signalingmolecules that regulate a variety of cellular phosphatase processesincluding cell growth, differentiation, mitotic cycle, N2 isoform 1 andoncogenic transformation. This PTP possesses an precursor extracellularregion, a single transmembrane region, and a single intracellularcatalytic domain, and thus represents a receptor-type PTP. The catalyticdomain of this PTP is most closely related to PTPRN/IA-2beta. This PTPand PTPRN are both found to be major autoantigens associated withinsulin- dependent diabetes mellitus. Three alternatively splicedtranscript variants of this gene, which encode distinct proteins, havebeen reported. [provided by RefSeq, July 2008]. Transcript Variant: Thisvariant (1) encodes the longest isoform (1). Publication Note: ThisRefSeq record includes a subset of the publications that are availablefor this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: U66702.1, AF007555.1[ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081,ERS025082 [ECO:0000350] RAB37 exonic 326624 ras-related Rab proteins arelow molecular mass GTPases that are critical 115 protein Rab-37regulators of vesicle trafficking. For additional background isoform 2information on Rab proteins, see MIM 179508. [supplied by OMIM, April2006]. Transcript Variant: This variant (2) represents use of analternate promoter, 5' UTR, and alternate start codon, and includes analternate coding exon, compared to variant 3. The resulting isoform (2)has a distinct and longer N-terminus, compared to isoform 3. Transcriptexon combination :: AK098068.1, BX332255.2 [ECO:0000332] RNAseq introns:: single sample supports all introns ERS025084, ERS025088 [ECO:0000348]RBFOX1 intronic 54715 RNA binding The Fox-1 family of RNA-bindingproteins is evolutionarily 116 protein fox-1 conserved, and regulatestissue-specific alternative splicing in homolog 1 metazoa. Fox-1recognizes a (U)GCAUG stretch in regulated isoform 1 exons or inflanking introns. The protein binds to the C- terminus of ataxin-2 andmay contribute to the restricted pathology of spinocerebellar ataxiatype 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causesfamilial neurodegenerative diseases. Fox-1 and ataxin-2 are bothlocalized in the trans-Golgi network. Several alternatively splicedtranscript variants encoding different isoforms have been found for thisgene. [provided by RefSeq, November 2011]. Transcript Variant: Thisvariant (1), also known as gamma, encodes the longest isoform (1).Sequence Note: This RefSeq record was created from transcript andgenomic sequence data because no single transcript was available for thefull length of the gene. The extent of this transcript is supported bytranscript alignments. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: AF229057.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025083, ERS025099 [ECO:0000348] RCC1 exonic 1104N/A N/A 117 RGCC exonic 28984 regulator of This gene is thought toregulate cell cycle progression. It is 118 cell cycle induced by p53 inresponse to DNA damage, or by sublytic RGCC levels of complement systemproteins that result in activation fof the cell cycle. The encodedprotein localizes to the cytoplasm during interphase and to centrosomesduring mitosis. The protein forms a complex with polo-like kinase 1. Theprotein also translocates to the nucleus in response to treatment withcomplement system proteins, and can associate with and increase thekinase activity of cell division cycle 2 protein. In different assaysand cell types, overexpression of this protein has been shown toactivate or suppress cell cycle progression. [provided by RefSeq, July2008]. Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::BC066334.1, BG037019.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025092 [ECO:0000348] RHOQ intronic23433 rho-related This gene encodes a member of the Rho family of small119 GTP-binding GTPases, which cycle between inactive GDP-bound andprotein RhoQ active GTP-bound states and function as molecular switchesprecursor in signal transduction cascades. Rho proteins promotereorganization of the actin cytoskeleton and regulate cell shape,attachment, and motility. The encoded protein is an important signallingprotein for sarcomere assembly and has been shown to play a significantrole in the exocytosis of the solute carrier family 2, facilitatedglucose transporter member 4 and other proteins, possibly acting as thesignal that turns on the membrane fusion machinery. Three relatedpseudogene have been identified on chromosomes 2 and 14. [provided byRefSeq, August 2011]. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: BX428852.2, BC013135.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025081, ERS025082 [ECO:0000348]RNASE3 exonic 6037 eosinophil IN/A 120 cationic protein precursorRNASE10 exonic 338879 inactive N/A 121 ribonuclease- like protein 10precursor RPL38 exonic 6169 60S ribosomal Ribosomes, the organelles thatcatalyze protein synthesis, 122 protein L38 consist of a small 40Ssubunit and a large 60S subunit. Together these subunits are composed of4 RNA species and approximately 80 structurally distinct proteins. Thisgene encodes a ribosomal protein that is a component of the 60S subunit.The protein belongs to the L38E family of ribosomal proteins. It islocated in the cytoplasm. Alternative splice variants have beenidentified, both encoding the same protein. As is typical for genesencoding ribosomal proteins, there are multiple processed pseudogenes ofthis gene dispersed through the genome, including one located in thepromoter region of the type 1 angiotensin II receptor gene. [provided byRefSeq, July 2008]. Transcript Variant: This variant (1) is the longerand predominant transcript. Variants 1 and 2 encode the same protein.Transcript exon combination :: BQ276548.1, BU569438.1 [ECO:0000332]RNAseq introns :: single sample supports all introns ERS025081,ERS025082 [ECO:0000348] RPTOR intronic 57521 regulatory- This geneencodes a component of a signaling pathway that 123 associated regulatescell growth in response to nutrient and insulin protein of levels. Theencoded protein forms a stoichiometric complex mTOR with the mTORkinase, and also associates with eukaryotic isoform 1 initiation factor4E-binding protein-1 and ribosomal protein S6 kinase. The proteinpositively regulates the downstream effector ribosomal protein S6kinase, and negatively regulates the mTOR kinase. Multiple transcriptvariants encoding different isoforms have been found for this gene.[provided by RefSeq, September 2009]. Transcript Variant: This variant(1) represents the longer transcript and encodes the longer isoform (1).Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::AY090663.1, BC136652.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025083, ERS025085 [ECO:0000348 SERPINB4 exonic6318 serpin B4 N/A 124 SERPINB6 exonic 5269 serpin B6 The proteinencoded by this gene is a member of the serpin 125 isoform a (serineproteinase inhibitor) superfamily, and ovalbumin(ov)- serpin subfamily.It was originally discovered as a placental thrombin inhibitor. Themouse homolog was found to be expressed in the hair cells of the innerear. Mutations in this gene are associated with nonsyndromic progressivehearing loss, suggesting that this serpin plays an important role in theinner ear in the protection against leakage of lysosomal content duringstress, and that loss of this protection results in cell death andsensorineural hearing loss. Alternatively spliced transcript variantshave been found for this gene. [provided by RefSeq, September 2010].Transcript Variant: This variant (1) represents the predominanttranscript. Variants 1, 5 and 6 encode the same isoform (a). PublicationNote: This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: AK314578.1, BC098564.1[ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081,ERS025082 ECO:00003501 SLC3A2 both 6520 4F2 cell- This gene is a memberof the solute carrier family and 126 surface encodes a cell surface,transmembrane protein. The protein antigen heavy exists as the heavychain of a heterodimer, covalently bound chain isoform throughdi-sulfide bonds to one of several possible light b chains. The encodedtransporter plays a role in regulation of intracellular calcium levelsand transports L-type amino acids. Alternatively spliced transcriptvariants, encoding different isoforms, have been characterized.[provided by RefSeq, November 2010]. Transcript Variant: This variant(2) represents the longest transcript and encodes the longest isoform(b). Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::AK025584.1 [ECO:0000332] RNAseq introns :: mixed/partial sample supportERS025082, ERS025084 [ECO:0000350] SLC17A5 both 26503 sialin This geneencodes a membrane transporter that exports free 127 sialic acids thathave been cleaved off of cell surface lipids and proteins fromlysosomes. Mutations in this gene cause sialic acid storage diseases,including infantile sialic acid storage disorder and Salla disease, anadult form. [provided by RefSeq, July 2008]. Publication Note: ThisRefSeq record includes a subset of the publications that are availablefor this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: BC020961.2, [AJ387747.1[ECO:0000332] RNAseq introns :: single sample supports all intronsERS025081, ERS025082 [ECO:0000348] SNHG3 exonic 8420 N/A N/A 128 SNORD17exonic 692086 N/A N/A 129 SNX5 exonic 27131 sorting nexin- This geneencodes a member of the sorting nexin family. 130 5 isoform a Members ofthis family contain a phox (PX) domain, which is a phosphoinositidebinding domain, and are involved in intracellular trafficking. Thisprotein functions in endosomal sorting, the phosphoinositide-signalingpathway, and macropinocytosis. This gene may play a role in thetumorigenesis of papillary thyroid carcinoma. Alternative splicingresults in multiple transcript variants encoding different isoforms.[provided by RefSeq, September 2013]. Transcript Variant: This variant(1) differs in the 5' UTR, compared to variant 2. Variants 1 and 2encode the same protein (isoform a). Transcript exon combination ::BC000100.3, AF121855.1 [ECO:0000332] RNAseq introns :: mixed/partialsample support ERS025081, ERS025082 [ECO:0000350] SOCS2 exonic 8835suppressor of This gene encodes a member of the suppressor of cytokine131 cytokine signaling (SOCS) family. SOCS family members are signaling2 cytokine-inducible negative regulators of cytokine receptor signalingvia the Janus kinase/signal transducer and activation of transcriptionpathway (the JAK/STAT pathway). SOCS family proteins interact with majormolecules of signaling complexes to block further signal transduction,in part, by proteasomal depletion of receptors or signal-transducingproteins via ubiquitination. The expression of this gene can be inducedby a subset of cytokines, including erythropoietin, GM-CSF, IL10,interferon (IFN)-gamma and by cytokine receptors such as growth horomonereceptor. The protein lencoded by this gene interacts with thecytoplasmic domain of insulin-like growth factor-1 receptor (IGF1R) andis thought to be involved in the regulation of IGFIR mediated cellsignaling. This gene has pseudogenes on chromosomes 20 and 22.Alternative splicing results in multiple transcript variants. [providedby RefSeq, July 2012]. Transcript Variant: This variant (1) differs inthe 5' UTR, compared to variant 5. Variants 1-6 encode the same protein.Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::AK313165.1, AL522912.3 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025082 [ECO:0000348] SOCS2-AS1 exonic144481 N/A N/A 132 ST8SIA5 exonic 29906 alpha-2,8- The protein encodedby this gene is a type II membrane 133 sialyltransferase protein thatmay be present in the Golgi apparatus. The 8E encoded protein, which isa member of glycosyltransferase family 29, may be involved in thesynthesis of gangliosides GD1c, GTla, GQ1b, and GT3 from GDIa, GT1b,GM1b, and GD3, respectively. [provided by RefSeq, July 2008]. Transcriptexon combination :: AK056270.1, BC108910.1 [ECO:0000332] RNAseq introns:: single sample supports all introns ERS025082, ERS025084 [ECO:0000348]STIM2 intronic 57620 stromal This gene is a member of the stromalinteraction molecule 134 interaction (STIM) family and likely arose,along with related family molecule 2 member STIM1, from a commonancestral gene. The encoded isoform 1 protein functions to regulatecalcium concentrations in the precursor cytosol and endoplasmicreticulum, and is involved in the activation of plasma membrane OraiCa(2+) entry channels. This gene initiates translation from a non-AUG(UUG) start site. A signal peptide is cleaved from the resultingprotein. Multiple transcript variants result from alternative splicing.[provided by RefSeq, December 2009]. Transcript Variant: This variant(1) encodes the longest isoform (1). Publication Note: This RefSeqrecord includes a subset of the publications that are available for thisgene. Please see the Gene record to access additional publications.Transcript exon combination :: BC136449.1, AK096846.1 [ECO:0000332]RNAseq introns :: single sample supports all introns ERS025081,ERS025084 [ECO:0000348] ##RefSeq-Attributes-START## CDS uses downstreamin-frame AUG :: experimental evidence (PMID:11463338) non-AUG initiationcodon :: PMID; 11463338 ##RefSeq-Attributes-END## TBC1D16 intronic125058 TBC1 domain N/A 136 family member 16 isoform a TEX29 exonic121793 testis- N/A 137 expressed sequence 29 protein TNFRSF10A exonic8797 tumor necrosis The protein encoded by this gene is a member of theTNF- 138 factor receptor receptor superfamily. This receptor isactivated by tumor superfamily necrosis factor-related apoptosisinducing ligand member 10A (TNFSF10/TRAIL), and thus transduces celldeath signal and induces cell apoptosis. Studies with FADD-deficientmice suggested that FADD, a death domain containing adaptor protein, isrequired for the apoptosis mediated by this protein. [provided byRefSeq,July 2008]. Publication Note: This RefSeq record includes a subset ofthe publications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::BC012866.1, AK291299.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025081, ERS025084 [ECO:0000348] TNFRSF13C exonic115650 tumor necrosis B cell-activating factor (BAFF) enhances B-cellsurvival in 139 factor receptor vitro and is a regulator of theperipheral B-cell population. superfamily Overexpression of Baff in miceresults in mature B-cell member 13C hyperplasia and symptoms of systemiclupus erythematosus (SLE). Also, some SLE patients have increased levelsof BAFF in serum. Therefore, it has been proposed that abnormally highlevels of BAFF may contribute to the pathogenesis of autoimmune diseasesby enhancing the survival of autoreactive B cells. The protein encodedby this gene is a receptor for BAFF and is a type III transmembraneprotein containing a single extracellular cysteine-rich domain. It isthought that this receptor is the principal receptor required forBAFF-mediated mature B-cell survival. [provided by RefSeq, July 2008].Sequence Note: The RefSeq transcript and protein were derived fromgenomic sequence to make the sequence consistent with the referencegenome assembly. The genomic coordinates used for the transcript recordwere based on alignments. Publication Note: This RefSeq record includesa subset of the publications that are available for this gene. Pleasesee the Gene record to access additional publications. Transcript exoncombination :: AF373846.1, BC112030.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025089 [ECO:0000348] TNFRSF18exonic 8784 tumor necrosis This gene encodes a member of theTNF-receptor 140 factor receptor superfamily. The encoded receptor hasbeen shown to have superfamily increased expression upon T-cellactivation, and it is thought member 18 to play a key role in dominantimmunological self-tolerance isoform 1 maintained by CD25(+)CD4(+)regulatory T cells. Knockout precursor studies in mice also suggest therole of this receptor is in the regulation of CD3-driven T-cellactivation and programmed cell death. Three alternatively splicedtranscript variants of this gene encoding distinct isoforms have beenreported. [provided by RefSeq, February 2011]. Transcript Variant: Thisvariant (1) represents the longest transcript. It contains an extracoding segment, which leads to a frame shift, compared to variant 2. Theresulting preotein (isoform 1) contains a distinct and shorterC-terminus, as compared to isoform 2. Sequence Note: This RefSeq recordwas created from transcript and genomic sequence data to make thesequence consistent with the reference genome assembly. The genomiccoordinates used for the transcript record were based on transcriptalignments. Publication Note: This RefSeq record includes a subset ofthe publications that are available for this gene. Please see the Generecord to access additional publications. Transcript exon combination ::AY358877.1, AF125304.1 [ECO:0000332] RNAseq introns :: single samplesupports all introns ERS025089, ERS025093 [ECO:0000348 TRAFD1 exonic10906 TRAF-type The innate immune system confers host defense againstviral 141 zinc finger and microbial infection, and TRAFDI is a negativefeedback domain- regulator that controls excessive immune responses(Sanada containing et al., 2008 [PubMed 18849341]). [supplied by OMIM,December protein 1 2009]. Transcript Variant: This variant (1)represents the longer transcript. Variants 1 and 2 both encode the sameprotein. Transcript exon combination :: AK122620.1 [ECO:0000332] RNAseqintrons :: single sample supports all introns ERS025083, ERS025084[ECO:0000348] TRPM2 exonic 7226 Transient The protein encoded by thisgene is a calcium-permeable 142 Receptor cation channel that isregulated by free intracellular ADP- Potential ribose. The encodedprotein is activated by oxidative stress Cation and conferssusceptibility to cell death. Several alternatively Channel splicedtranscript variants of this gene have been described, Subfamily M buttheir full-length nature is not known. [provided by Member 2 RefSeq,July 2008]. Transcript Variant: This variant (2) uses an alternatein-frame splice junction at the 5' end of an exon compared to variant 1.This results in the introduction of a premature stop codon and rendersthe transcript a nonsense- mediated mRNA decay (NMD) candidate.Therefore, this transcript is not thought to be protein-coding.Publication Note: This RefSeq record includes a subset of thepublications that are available for this gene. Please see the Generecord to access additional publications. RNAseq introns ::mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] TTLL10exonic 254173 inactive N/A 143 polyglycylase TTLL10 isoform 1 TTYH2exonic 94015 protein tweety This gene encodes a member of the tweetyfamily of proteins. 144 homolog 2 Members of this family function aschloride anion channels. isoform 1 The encoded protein functions as acalcium(2+)-activated large conductance chloride(-) channel, and mayplay a role in kidney tumorigenesis. Two transcript variants encodingdistinct isoforms have been identified for this gene. [provided byRefSeq, July 2008]. Transcript Variant: This variant (1) represents thelonger transcript, and encodes the longer isoform (1). Transcript exoncombination :: AF319952.1, BC107492.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025082, ERS025083 [ECO:0000348]UBE2N exonic 7334 ubiquitin- The modification of proteins with ubiquitinis an important 145 conjugating cellular mechanism for targetingabnormal or short-lived enzyme E2 N proteins for degradation.Ubiquitination involves at least three classes of enzymes:ubiquitin-activating enzymes, or Els, ubiquitin-conjugating enzymes, orE2s, and ubiquitin-protein ligases, or E3s. This gene encodes a memberof the E2 ubiquitin-conjugating enzyme family. Studies in mouse suggestthat this protein plays a role in DNA postreplication repair. [providedby RefSeq, July 2008]. Publication Note: This RefSeq record includes asubset of the publications that are available for this gene. Please seethe Gene record to access additional publications. Transcript exoncombination :: BC000396.2, D83004.1 [ECO:0000332] RNAseq introns ::single sample supports all introns ERS025084 [ECO:0000348] VCX exonic26609 variable charge This gene belongs to the VCX/Y gene family, whichhas 146 X-linked [multiple members on both X and Y chromosomes, and allare protein 1 expressed exclusively in male germ cells. The X-linkedmembers are clustered on chromosome Xp22 and Y-linked members are twoidentical copies of the gene within a palindromic region on Yq11. Thefamily members share a high degree of sequence identity, with theexception that a 30- bp unit is tandemly repeated in X-linked membersbut occurs only once in Y-linked members. The VCX gene cluster ispolymorphic in terms of copy number; different individuals may have adifferent number of VCX genes. VCX/Y genes encode small and highlycharged proteins of unknown function. The presence of a putativebipartite nuclear localization signal suggests that VCX/Y members arenuclear proteins. This gene contains 10 repeats of the 30-bp unit.[provided by RefSeq, July 2008]. Transcript exon combination ::AF167081.2 [ECO:0000332] VSTM1 intronic 284415 V-set and N/A 147transmembrane domain- containing protein 1 precursor VWA2 exonic 340706von This gene encodes a member of the von Willebrand factor A- 148Willebrand like domain protein superfamily. The encoded protein isfactor A localized to the extracellular matrix and may serve as adomain- structural component in basement membranes or in anchoringcontaining structures on scaffolds of collagen VII or fibrillin. Thisgene protein 2 has been linked to type 1A diabetes and is a candidateprecursor serological marker for colon cancer. [provided by RefSeq,January 2013]. Sequence Note: This RefSeq record was created fromtranscript and genomic sequence data to make the sequence consistentwith the reference genome assembly. The genomic coordinates used for thetranscript record were based on transcript alignments. CCDS Note: Thecoding region has been updated to represent an alternative 3' splicingpattern that is more supported by the available transcript and proteindata. Transcript exon combination :: AY572972.1, AJ536328.2[ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081,ERS025084 [ECO:0000350] ZNF350 exonic 59348 zinc finger N/A 149 protein350 ZNF432 exonic 9668 zinc finger N/A 150 protein 432 ZNF577 exonic84765 N/A N/A 151 ZNF613 exonic 79898 zinc finger N/A 152 protein 613isoform 1 ZNF614 exonic 80110 zinc finger N/A 153 protein 614 ZNF615exonic 284370 zinc finger N/A 154 protein 615 isoform 1 ZNF649 exonic65251 zinc finger N/A 155 protein 649 ZNF841 exonic 284371 zinc fingerN/A 156 protein 841

For all genes listed in Table 2 (namely, those relevant toCNV-subregions of interest), Table 3 represents a non-redundant list.

TABLE 4 A non-redundant list of transcript variants that correspond tothe genes in Table 3 RefSeq RefSeq Gene Exon Accession SEQ Symboloverlap Number mRNA Description ID MIR200B exonic NR 029639 Homo sapiensmicroRNA 200b (MIR200B), microRNA. 173 MIR200A exonic NR 029834 Homosapiens microRNA 200a (MIR200A), microRNA. 174 MIR429 exonic NR 029957Homo sapiens microRNA 429 (MIR429), microRNA. 175 TTLL10 exonic NM001130045 Homo sapiens tubulin tyrosine ligase-like family, member 10176 (TTLL10), transcript variant 1, mRNA. TTLL10 exonic NM 153254 Homosapiens tubulin tyrosine ligase-like family, member 10 177 (TTLL10),transcript variant 2, mRNA. TNFRSF18 exonic NM 004195 Homo sapiens tumornecrosis factor receptor superfamily, member 178 18 (TNFRSF18),transcript variant 1, mRNA. TNFRSF18 exonic NM 148901 Homo sapiens tumornecrosis factor receptor superfamily, member 179 18 (TNFRSF18),transcript variant 2, mRNA. TNFRSF18 exonic NM 148902 Homo sapiens tumornecrosis factor receptor superfamily, member 180 18 (TNFRSF18),transcript variant 3, mRNA. PIK3CD exonic NM 005026 Homo sapiensphosphatidylinositol-4,5-bisphosphate 3-kinase, 181 catalytic subunitdelta (PIK3CD), mRNA. CAPZB intronic NR 038125 Homo sapiens cappingprotein (actin filament) muscle Z-line, beta 182 (CAPZB), transcriptvariant 4, non-coding RNA. CAPZB intronic NM 001206540 Homo sapienscapping protein (actin filament) muscle Z-line, beta 183 (CAPZB),transcript variant 2, mRNA. CAPZB intronic NM 004930 Homo sapienscapping protein (actin filament) muscle Z-line, beta 184 (CAPZB),transcript variant 1, mRNA. IFNLR1 exonic NM 170743 Homo sapiensinterferon, lambda receptor 1 (IFNLR1), transcript 185 variant 1, mRNA.IFNLR1 exonic NM 173064 Homo sapiens interferon, lambda receptor 1(IFNLR1), transcript 186 variant 2, mRNA. IFNLR1 exonic NM 173065 Homosapiens interferon, lambda receptor 1 (IFNLR1), transcript 187 variant3, mRNA. PHACTR4 exonic NM 001048183 Homo sapiens phosphatase and actinregulator 4 (PHACTR4), 188 transcript variant 1, mRNA. PHACTR4 exonic NM023923 Homo sapiens phosphatase and actin regulator 4 (PHACTR4), 189transcript variant 2, mRNA. SNHG3 exonic NR 002909 Homo sapiens smallnucleolar RNA host gene 3 (non-protein 190 coding) (SNHG3), transcriptvariant 2, non-coding RNA. SNHG3 exonic NR 036473 Homo sapiens smallnucleolar RNA host gene 3 (non-protein 191 coding) (SNHG3), transcriptvariant 1, non-coding RNA. RCC1 exonic NM 001048199 Homo sapiensregulator of chromosome condensation 1 (RCC1), 192 transcript variant 4,mRNA. RCC1 exonic NR 030725 Homo sapiens regulator of chromosomecondensation 1 (RCC1), 193 transcript variant 5, non-coding RNA. RCC1exonic NR 030726 Homo sapiens regulator of chromosome condensation 1(RCC1), 194 transcript variant 6, non-coding RNA. RCC1 exonic NM001048194 Homo sapiens regulator of chromosome condensation 1 (RCC1),195 transcript variant 1, mRNA. RCC1 exonic NM 001048195 Homo sapiensregulator of chromosome condensation 1 (RCC1), 196 transcript variant 2,mRNA. RCC1 exonic NM 001269 Homo sapiens regulator of chromosomecondensation 1 (RCC1), 197 transcript variant 3, mRNA. AGBL4 intronic NM032785 Homo sapiens ATP/GTP binding protein-like 4 (AGBL4), mRNA. 198GPATCH2 intronic NM 018040 Homo sapiens G patch domain containing 2(GPATCH2), mRNA. 199 RHOQ intronic NM 012249 Homo sapiens ras homologfamily member Q (RHOQ), mRNA. 200 PNPT1 both NM 033109 Homo sapienspolyribonucleotide nucleotidyltransferase 1 201 (PNPT1), mRNA. MCEE bothNM 032601 Homo sapiens methylmalonyl CoA epimerase (MCEE), mRNA. 202 HK2exonic NM 000189 Homo sapiens hexokinase 2 (HK2), mRNA. 203 FHL2 exonicNM 201557 Homo sapiens four and a half LIM domains 2 (FHL2), transcript204 variant 4, mRNA. FHL2 intronic NM 001039492 Homo sapiens four and ahalf LIM domains 2 (FHL2), transcript 205 variant 5, mRNA. FHL2 intronicNM 001450 Homo sapiens four and a half LIM domains 2 (FHL2), transcript206 variant 1, mRNA. FHL2 intronic NM 201555 Homo sapiens four and ahalf LIM domains 2 (FHL2), transcript 207 variant 2, mRNA. MIR4267exonic NR 036225 Homo sapiens microRNA 4267 (MIR4267), microRNA. 208MALL exonic NM 005434 Homo sapiens mal, T-cell differentiationprotein-like (MALL), 209 mRNA. MIR4436B1 exonic NR 039941 Homo sapiensmicroRNA 4436b-1 (MIR4436B1), microRNA. 210 MIR4436B2 exonic NR 049830Homo sapiens microRNA 4436b-2 (MIR4436B2), microRNA. 211 MGAT5 intronicNM 002410 Homo sapiens mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-212 acetyl-glucosaminyltransferase (MGAT5), mRNA. BMPR2 intronic NM001204 Homo sapiens bone morphogenetic protein receptor, type II 213serine/threonine kinase) (BMPR2), mRNA. DNER intronic NM 139072 Homosapiens delta/notch-like EGF repeat containing (DNER), 214 mRNA. IQCB1exonic NM 001023570 Homo sapiens IQ motif containing B1 (IQCB1),transcript variant 215 1, mRNA. IQCB1 exonic NM 001023571 Homo sapiensIQ motif containing B1 (IQCB1), transcript variant 216 3, mRNA. STIM2intronic NM 001169117 Homo sapiens stromal interaction molecule 2(STIM2), transcript 217 variant 3, mRNA. STIM2 intronic NM 001169118Homo sapiens stromal interaction molecule 2 (STIM2), transcript 218variant 1, mRNA. STIM2 intronic NM 020860 Homo sapiens stromalinteraction molecule 2 (STIM2), transcript 219 variant 2, mRNA. PDGFRAexonic NM 006206 Homo sapiens platelet-derived growth factor receptor,alpha 220 polypeptide (PDGFRA), mRNA. HCN1 exonic NM 021072 Homo sapienshyperpolarization activated cyclic nucleotide-gated 221 potassiumchannel 1 (HCN1), mRNA. EMB exonic NM 198449 Homo sapiens embigin (EMB),mRNA. 222 EDIL3 intronic NM 005711 Homo sapiens EGF-like repeats anddiscoidin I-like domains 3 223 (EDIL3), transcript variant 1, mRNA.MAPK9 exonic NM 002752 Homo sapiens mitogen-activated protein kinase 9(MAPK9), 224 transcript variant JNK2-a2, mRNA. MAPK9 exonic NM 139068Homo sapiens mitogen-activated protein kinase 9 (MAPK9), 225 transcriptvariant JNK2-al, mRNA. MAPK9 exonic NM 139069 Homo sapiensmitogen-activated protein kinase 9 (MAPK9), 226 transcript variantJNK2-b1, mRNA. MAPK9 exonic NM 139070 Homo sapiens mitogen-activatedprotein kinase 9 (MAPK9), 227 transcript variant JNK2-b2, mRNA. MAPK9exonic NM 001135044 Homo sapiens mitogen-activated protein kinase 9(MAPK9), 228 transcript variant JNK2-g, mRNA. SERPINB6 exonic NM001271825 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin),229 member 6 (SERPINB6), transcript variant 6, mRNA. SERPINB6 exonic NM001271823 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin),230 member 6 (SERPINB6), transcript variant 4, mRNA. SERPINB6 exonic NM001271822 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin),231 member 6 (SERPINB6), transcript variant 3, mRNA. SERPINB6 exonic NM001195291 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin),232 member 6 (SERPINB6), transcript variant 2, mRNA. SERPINB6 exonic NM001271824 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin),233 member 6 (SERPINB6), transcript variant 5, mRNA. SERPINB6 exonic NM004568 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 234member 6 (SERPINB6), transcript variant 1, mRNA. DKFZP686I exonic NR026855 Homo sapiens long intergenic non-protein coding RNA 1011 23515217 (LINC01011), transcript variant 1, non-coding RNA. DKFZP686Iexonic NR 026856 Homo sapiens long intergenic non-protein coding RNA1011 236 15217 (LINC01011), transcript variant 2, non-coding RNA. NQO2exonic NM 000904 Homo sapiens NAD(P)H dehydrogenase, quinone 2 (NQO2),237 mRNA. HTATSFIP2 exonic NR 033884 Homo sapiens HIV-1 Tat specificfactor 1 pseudogene 2 238 (HTATSF1P2), non-coding RNA. PKHD1 intronic NM138694 Homo sapiens polycystic kidney and hepatic disease 1 (autosomal239 recessive) (PKHD1), transcript variant 1, mRNA. PKHD1 intronic NM170724 Homo sapiens polycystic kidney and hepatic disease 1 (autosomal240 recessive) (PKHD1), transcript variant 2, mRNA. SLC17A5 both NM012434 Homo sapiens solute carrier family 17 (acidic sugar transporter),241 member 5 (SLC17A5), mRNA. PDSS2 exonic NM 020381 Homo sapiens prenyl(decaprenyl) diphosphate synthase, subunit 2 242 (PDSS2), mRNA. KCTD7exonic NM 001167961 Homo sapiens potassium channel tetramerizationdomain 243 containing 7 (KCTD7), transcript variant 2, mRNA. KCTD7exonic NM 153033 Homo sapiens potassium channel tetramerization domain244 containing 7 (KCTD7), transcript variant 1, mRNA. PTPRN2 intronic NM002847 Homo sapiens protein tyrosine phosphatase, receptor type, N 245polypeptide 2 (PTPRN2), transcript variant 1, mRNA. PTPRN2 intronic NM130842 Homo sapiens protein tyrosine phosphatase, receptor type, N 246polypeptide 2 (PTPRN2), transcript variant 2, mRNA. PTPRN2 intronic NM130843 Homo sapiens protein tyrosine phosphatase, receptor type, N 247polypeptide 2 (PTPRN2), transcript variant 3, mRNA. MIR595 exonic NR030325 Homo sapiens microRNA 595 (MIR595), microRNA. 248 TNFRSF10 exonicNM 003844 Homo sapiens tumor necrosis factor receptor superfamily,member 249 A 10a (TNFRSF10A), mRNA. IDO2 intronic NM 194294 Homo sapiensindoleamine 2,3-dioxygenase 2 (IDO2), mRNA. 250 STK3 intronic NM001256313 Homo sapiens serine/threonine kinase 3 (STK3), transcriptvariant 251 3, mRNA. STK3 intronic NM 006281 Homo sapiensserine/threonine kinase 3 (STK3), transcript variant 252 1, mRNA. STK3intronic NM 001256312 Homo sapiens serine/threonine kinase 3 (STK3),transcript variant 253 2, mRNA. KANK1 intronic NM 001256876 Homo sapiensKN motif and ankyrin repeat domains 1 (KANK1), 254 transcript variant 3,mRNA. KANK1 intronic NM 001256877 Homo sapiens KN motif and ankyrinrepeat domains 1 (KANK1), 255 transcript variant 4, mRNA. KANK1 intronicNM 015158 Homo sapiens KN motif and ankyrin repeat domains 1 (KANK1),256 transcript variant 1, mRNA. KANK1 intronic NM 153186 Homo sapiens KNmotif and ankyrin repeat domains 1 (KANK1), 257 transcript variant 2,mRNA. GDA exonic NM 001242507 Homo sapiens guanine deaminase (GDA),transcript variant 4, 258 mRNA. GDA exonic NM 001242505 Homo sapiensguanine deaminase (GDA), transcript variant 1, 259 mRNA. GDA exonic NM001242506 Homo sapiens guanine deaminase (GDA), transcript variant 3,260 mRNA. GDA exonic NM 004293 Homo sapiens guanine deaminase (GDA),transcript variant 2, 261 mRNA. AUH exonic NM 001698 Homo sapiens AU RNAbinding protein/enoyl-CoA hydratase 262 (AUH), mRNA. MIR3163 exonic NR036121 Homo sapiens microRNA 3163 (MIR3163), microRNA. 263 NFIL3 exonicNM 005384 Homo sapiens nuclear factor, interleukin 3 regulated (NFIL3),264 mRNA. MIR3910-1 exonic NR 037472 Homo sapiens microRNA 3910-1(MIR3910-1), microRNA. 265 MIR3910-2 exonic NR 037489 Homo sapiensmicroRNA 3910-2 (MIR3910-2), microRNA. 266 ASTN2 intronic NM 014010 Homosapiens astrotactin 2 (ASTN2), transcript variant 1, mRNA. 267 ASTN2intronic NM 198186 Homo sapiens astrotactin 2 (ASTN2), transcriptvariant 2, mRNA. 268 ASTN2 intronic NM 001184734 Homo sapiensastrotactin 2 (ASTN2), transcript variant 5, mRNA. 269 ASTN2 intronic NM198187 Homo sapiens astrotactin 2 (ASTN2), transcript variant 3, mRNA.270 ASTN2 intronic NM 198188 Homo sapiens astrotactin 2 (ASTN2),transcript variant 4, mRNA. 271 ASTN2 intronic NM 001184735 Homo sapiensastrotactin 2 (ASTN2), transcript variant 6, mRNA. 272 LARP4B exonic NM015155 Homo sapiens La ribonucleoprotein domain family, member 4B 273(LARP4B), mRNA. GTPBP4 exonic NM 012341 Homo sapiens GTP binding protein4 (GTPBP4), mRNA. 274 IDI2 exonic NM 033261 Homo sapiensisopentenyl-diphosphate delta isomerase 2 (IDI2), 275 mRNA. IDI2-AS1exonic NR 024628 Homo sapiens IDI2 antisense RNA 1 (IDI2-AS1),transcript variant 276 1. non-coding RNA. IDI2-AS1 exonic NR 024629 Homosapiens IDI2 antisense RNA 1 (IDI2-AS1), transcript variant 277 2,non-coding RNA. IDI2-AS1 exonic NR 027708 Homo sapiens IDI2 antisenseRNA 1 (IDI2-AS1), transcript variant 278 3, non-coding RNA. IDI2-AS1exonic NR 027709 Homo sapiens IDI2 antisense RNA 1 (IDI2-AS1),transcript variant 279 4, non-coding RNA. KAT6B exonic NM 001256468 Homosapiens K(lysine) acetyltransferase 6B (KAT6B), transcript 280 variant2, mRNA. KAT6B exonic NM 001256469 Homo sapiens K(lysine)acetyltransferase 6B (KAT6B), transcript 281 variant 3, mRNA. KAT6Bexonic NM 012330 Homo sapiens K(lysine) acetyltransferase 6B (KAT6B),transcript 282 variant 1, mRNA. VWA2 exonic NM 001272046 Homo sapiensvon Willebrand factor A domain containing 2 283 (VWA2), mRNA. PDE3Bintronic NM 000922 Homo sapiens phosphodiesterase 3B, cGMP-inhibited(PDE3B), 284 ImRNA. EHF intronic NM 001206615 Homo sapiens etshomologous factor (EHF), transcript variant 3, 285 mRNA. EHF intronic NM012153 Homo sapiens ets homologous factor (EHF), transcript variant 2,286 mRNA. EHF exonic NM 001206616 Homo sapiens ets homologous factor(EHF), transcript variant 1, 287 mRNA. SLC3A2 exonic NM 001012662 Homosapiens solute carrier family 3 (amino acid transporter heavy 288chain), member 2 (SLC3A2), transcript variant 2, mRNA. SLC3A2 intronicNM 001012664 Homo sapiens solute carrier family 3 (amino acidtransporter heavy 289 chain), member 2 (SLC3A2), transcript variant 5,mRNA. SLC3A2 exonic NM 002394 Homo sapiens solute carrier family 3(amino acid transporter heavy 290 chain), member 2 (SLC3A2), transcriptvariant 3, mRNA. SLC3A2 intronic NM 001013251 Homo sapiens solutecarrier family 3 (amino acid transporter heavy 291 chain), member 2(SLC3A2), transcript variant 6, mRNA. SLC3A2 intronic NR 037193 Homosapiens solute carrier family 3 (amino acid transporter heavy 292chain), member 2 (SLC3A2), transcript variant 7, non-coding RNA. GDPD4exonic NM 182833 Homo sapiens glycerophosphodiester phosphodiesterasedomain 293 containing 4 (GDPD4), mRNA. ETV6 exonic NM 001987 Homosapiens ets variant 6 (ETV6), mRNA. 294 LOH12CR1 exonic NM 058169 Homosapiens loss of heterozygosity, 12, chromosomal region 1 295 (LOH12CRI),mRNA. DUSP16 exonic NM 030640 Homo sapiens dual specificity phosphatase16 (DUSP16), mRNA. 296 CREBL2 exonic NM 001310 Homo sapiens cAMPresponsive element binding protein-like 2 297 (CREBL2), mRNA. GPR19exonic NM 006143 Homo sapiens G protein-coupled receptor 19 (GPR19),mRNA. 298 CDKN1B exonic NM 004064 Homo sapiens cyclin-dependent kinaseinhibitor 1B (p27, Kip1) 299 (CDKN1B), mRNA. APOLD1 exonic NM 001130415Homo sapiens apolipoprotein L domain containing 1 (APOLD1), 300transcript variant 1, mRNA. APOLD1 intronic NM 030817 Homo sapiensapolipoprotein L domain containing 1 (APOLD1), 301 transcript variant 2,mRNA. EEA1 exonic NM 003566 Homo sapiens early endosome antigen 1(EEA1), mRNA. 302 LOC643339 exonic NR 040096 Homo sapiensuncharacterized LOC643339 (LOC643339), non- 303 coding RNA. NUDT4 exonicNM 019094 Homo sapiens nudix (nucleoside diphosphate linked moietyX)-type 304 motif 4 (NUDT4), transcript variant 1, mRNA. NUDT4 exonic NM199040 Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type305 motif 4 (NUDT4), transcript variant 2, mRNA. NUDT4P1 exonic NR002212 Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type306 motif 4 pseudogene I (NUDT4P1), non-coding RNA. UBE2N exonic NM003348 Homo sapiens ubiquitin-conjugating enzyme E2N (UBE2N), 307 mRNA.MRPL42 exonic NM 014050 Homo sapiens mitochondrial ribosomal protein L42(MRPL42), 308 transcript variant 1, mRNA. MRPL42 exonic NM 172177 Homosapiens mitochondrial ribosomal protein L42 (MRPL42), 309 transcriptvariant 2, mRNA. MRPL42 exonic NR 038159 Homo sapiens mitochondrialribosomal protein L42 (MRPL42), 310 transcript variant 3, non-codingRNA. MRPL42 exonic NR 038160 Homo sapiens mitochondrial ribosomalprotein L42 (MRPL42), 311 transcript variant 4, non-coding RNA. MRPL42exonic NR 038161 Homo sapiens mitochondrial ribosomal protein L42(MRPL42), 312 transcript variant 5, non-coding RNA. SOCS2-AS1 exonic NR038263 Homo sapiens SOCS2 antisense RNA 1 (SOCS2-AS1), non-coding 313RNA. SOCS2 exonic NM 003877 Homo sapiens suppressor of cytokinesignaling 2 (SOCS2), 314 transcript variant 1, mRNA. SOCS2 exonic NM001270467 Homo sapiens suppressor of cytokine signaling 2 (SOCS2), 315transcript variant 2, mRNA. SOCS2 exonic NM 001270468 Homo sapienssuppressor of cytokine signaling 2 (SOCS2), 316 transcript variant 3,mRNA. SOCS2 exonic NM 001270469 Homo sapiens suppressor of cytokinesignaling 2 (SOCS2), 317 transcript variant 4, mRNA. SOCS2 exonic NM001270470 Homo sapiens suppressor of cytokine signaling 2 (SOCS2), 318transcript variant 5, mRNA. SOCS2 exonic NM 001270471 Homo sapienssuppressor of cytokine signaling 2 (SOCS2), 319 transcript variant 6,mRNA. CRADD exonic NM 003805 Homo sapiens CASP2 and RIPKI domaincontaining adaptor with 320 death domain (CRADD), mRNA. PLXNC1 exonic NM005761 Homo sapiens plexin C1 (PLXNC1), transcript variant 1, mRNA. 321PLXNC1 exonic NR 037687 Homo sapiens plexin C1 (PLXNC1), transcriptvariant 2, non- 322 coding RNA. CCDC41 exonic NM 001042399 Homo sapienscoiled-coil domain containing 41 (CCDC41), 323 transcript variant 2,mRNA. CCDC41 exonic NM 016122 Homo sapiens coiled-coil domain containing41 (CCDC41), 324 transcript variant 1, mRNA. TRAFD1 exonic NM 001143906Homo sapiens TRAF-type zinc finger domain containing 1 325 (TRAFD1),transcript variant 1, mRNA. TRAFD1 exonic NM 006700 Homo sapiensTRAF-type zinc finger domain containing 1 326 (TRAFD1), transcriptvariant 2, mRNA. RGCC exonic NM 014059 Homo sapiens regulator of cellcycle (RGCC), mRNA. 327 COMMD6 exonic NM 203495 Homo sapiens COMM domaincontaining 6 (COMMD6), transcript 328 variant 2, mRNA. COMMD6 exonic NM203497 Homo sapiens COMM domain containing 6 (COMMD6), transcript 329variant 1, mRNA. GPC5 intronic NM 004466 Homo sapiens glypican 5 (GPC5),mRNA. 330 ARHGEF7 exonic NM 003899 Homo sapiens Rho guanine nucleotideexchange factor (GEF) 7 331 (ARHGEF7), transcript variant 1, mRNA.ARHGEF7 exonic NM 001113513 Homo sapiens Rho guanine nucleotide exchangefactor (GEF) 7 332 (ARHGEF7), transcript variant 5, mRNA. TEX29 exonicNM 152324 Homo sapiens testis expressed 29 (TEX29), mRNA. 333 ARHGEF7intronic NM 001113511 Homo sapiens Rho guanine nucleotide exchangefactor (GEF) 7 334 (ARHGEF7), transcript variant 3, mRNA. ARHGEF7intronic NM 001113512 Homo sapiens Rho guanine nucleotide exchangefactor (GEF) 7 335 (ARHGEF7), transcript variant 4, mRNA. ARHGEF7intronic NM 145735 Homo sapiens Rho guanine nucleotide exchange factor(GEF) 7 336 (ARHGEF7), transcript variant 2, mRNA. RNASE10 exonic NM001012975 Homo sapiens ribonuclease, RNase A family, 10 (non-active) 337(RNASE10), mRNA. RNASE3 exonic NM 002935 Homo sapiens ribonuclease,RNase A family, 3 (RNASE3), 338 mRNA. ECRP exonic NR 033909 Homo sapiensribonuclease, RNase A family, 2 (liver, eosinophil- 339 derivedneurotoxin) pseudogene (ECRP), non-coding RNA. PRKCH intronic NM 006255Homo sapiens protein kinase C, eta (PRKCH), mRNA. 340 MTHFD1 exonic NM005956 Homo sapiens methylenetetrahydrofolate dehydrogenase (NADP+ 341dependent) 1, methenyltetrahydrofolate cyclohydrolase,formyltetrahydrofolate synthetase (MTHFD1), mRNA. BDKRB2 intronic NM000623 Homo sapiens bradykinin receptor B2 (BDKRB2), mRNA. 342 HEXAexonic NM 000520 Homo sapiens hexosaminidase A (alpha polypeptide)(HEXA), 343 mRNA. PSTPIP1 exonic NM 003978 Homo sapiensproline-serine-threonine phosphatase interacting 344 protein 1(PSTPIP1), mRNA. RBFOX1 intronic NM 001142333 Homo sapiens RNA bindingprotein, fox-1 homolog (C. elegans) 1 345 (RBFOX1), transcript variant5, mRNA. RBFOX1 intronic NM 018723 Homo sapiens RNA binding protein,fox-1 homolog (C. elegans) 1 346 (RBFOX1), transcript variant 4, mRNA.RBFOX1 intronic NM 001142334 Homo sapiens RNA binding protein, fox-1homolog (C. elegans) 1 347 (RBFOX1), transcript variant 6, mRNA. RBFOX1intronic NM 145891 Homo sapiens RNA binding protein, fox-1 homolog (C.elegans) 1 348 (RBFOX1), transcript variant 1, mRNA. RBFOX1 intronic NM145892 Homo sapiens RNA binding protein, fox-1 homolog (C. elegans) I349 (RBFOX1), transcript variant 2, mRNA. RBFOX1 intronic NM 145893 Homosapiens RNA binding protein, fox-1 homolog (C. elegans) 1 350 (RBFOX1),transcript variant 3, mRNA. PRKCB both NM 002738 Homo sapiens proteinkinase C, beta (PRKCB), transcript variant 2, 351 mRNA. PRKCB both NM212535 Homo sapiens protein kinase C, beta (PRKCB), transcript variant1, 352 mRNA. FUK both NM 145059 Homo sapiens fucokinase (FUK), mRNA. 353COG4 exonic NM 001195139 Homo sapiens component of oligomeric golgicomplex 4 (COG4), 354 transcript variant 2, mRNA. COG4 exonic NM 015386Homo sapiens component of oligomeric golgi complex 4 (COG4), 355transcript variant 1, mRNA. HPR exonic NM 020995 Homo sapienshaptoglobin-related protein (HPR), mRNA. 356 RPL38 exonic NM 000999 Homosapiens ribosomal protein L38 (RPL38), transcript variant 1, 357 mRNA.RPL38 exonic NM 001035258 Homo sapiens ribosomal protein L38 (RPL38),transcript variant 2, 358 mRNA. MGC16275 exonic NR 026914 Homo sapiensuncharacterized protein MGC16275 (MGC16275), 359 non-coding RNA. TTYH2exonic NM 032646 Homo sapiens tweety family member 2 (TTYH2), transcriptvariant 360 1, mRNA. TTYH2 exonic NM 052869 Homo sapiens tweety familymember 2 (TTYH2), transcript variant 361 2, mRNA. DNAI2 exonic NM001172810 Homo sapiens dynein, axonemal, intermediate chain 2 (DNAI2),362 transcript variant 2, mRNA. DNAI2 exonic NM 023036 Homo sapiensdynein, axonemal, intermediate chain 2 (DNAI2), 363 transcript variant1, mRNA. KIF19 exonic NM 153209 Homo sapiens kinesin family member 19(KIF19), mRNA. 364 BTBD17 exonic NM 001080466 Homo sapiens BTB (POZ)domain containing 17 (BTBD17), 365 mRNA. GPR142 exonic NM 181790 Homosapiens G protein-coupled receptor 142 (GPR142), mRNA. 366 GPRC5C exonicNM 022036 Homo sapiens G protein-coupled receptor, family C, group 5,367 member C (GPRCSC), transcript variant 1, mRNA. GPRC5C exonic NM018653 Homo sapiens G protein-coupled receptor, family C, group 5, 368member C (GPRCSC), transcript variant 2, mRNA. CD300A exonic NM001256841 Homo sapiens CD300a molecule (CD300A), transcript variant 2,369 mRNA. CD300A exonic NM 007261 Homo sapiens CD300a molecule (CD300A),transcript variant 1, 370 mRNA. CD300LB exonic NM 174892 Homo sapiensCD300 molecule-like family member b (CD300LB), 371 mRNA. CD300C exonicNM 006678 Homo sapiens CD300c molecule (CD300C), mRNA. 372 CD300LDexonic NM 001115152 Homo sapiens CD300 molecule-like family member d(CD300LD), 373 mRNA. C17orf77 exonic NM 152460 Homo sapiens chromosome17 open reading frame 77 (C17orf77), 374 mRNA CD300E exonic NM 181449Homo sapiens CD300e molecule (CD300E), mRNA. 375 RAB37 exonic NM 175738Homo sapiens RAB37, member RAS oncogene family (RAB37), 376 transcriptvariant 3, mRNA. CD300LF exonic NM 139018 Homo sapiens CD300molecule-like family member f (CD300LF), 377 mRNA. RAB37 intronic NM001163989 Homo sapiens RAB37, member RAS oncogene family (RAB37), 378transcript variant 4, mRNA. RAB37 intronic NM 001006638 Homo sapiensRAB37, member RAS oncogene family (RAB37), 379 transcript variant 2,mRNA. RAB37 intronic NM 001163990 Homo sapiens RAB37, member RASoncogene family (RAB37), 380 transcript variant 5, mRNA. TBC1D16intronic NM 019020 Homo sapiens TBC1 domain family, member 16 (TBC1D16),381 transcript variant 1, mRNA. TBC1D16 intronic NM 001271844 Homosapiens TBC1 domain family, member 16 (TBC1D16), 382 transcript variant2, mRNA. TBC1D16 intronic NM 001271845 Homo sapiens TBC1 domain family,member 16 (TBC1D16), 383 transcript variant 3, mRNA. TBC1D16 intronic NM001271846 Homo sapiens TBC1 domain family, member 16 (TBC1D16), 384transcript variant 4, mRNA. RPTOR intronic NM 001163034 Homo sapiensregulatory associated protein of MTOR, complex 1 385 (RPTOR), transcriptvariant 2, mRNA. RPTOR intronic NM 020761 Homo sapiens regulatoryassociated protein of MTOR, complex 1 386 (RPTOR), transcript variant 1,mRNA. PTPN2 exonic NM 001207013 Homo sapiens protein tyrosinephosphatase, non-receptor type 2 387 (PTPN2), transcript variant 4,mRNA. PTPN2 exonic NM 080422 Homo sapiens protein tyrosine phosphatase,non-receptor type 2 388 (PTPN2), transcript variant 2, mRNA. PTPN2exonic NM 080423 Homo sapiens protein tyrosine phosphatase, non-receptortype 2 389 (PTPN2), transcript variant 3, mRNA. PTPN2 intronic NM 002828Homo sapiens protein tyrosine phosphatase, non-receptor type 2 390(PTPN2), transcript variant 1, mRNA. ST8SIA5 exonic NM 013305 Homosapiens ST8 alpha-N-acetyl-neuraminide alpha-2,8- 391 sialyltransferase5 (ST8SIA5), mRNA. PIAS2 exonic NM 004671 Homo sapiens protein inhibitorof activated STAT, 2 (PIAS2), 392 transcript variant beta, mRNA. PIAS2exonic NM 173206 Homo sapiens protein inhibitor of activated STAT, 2(PIAS2), 393 transcript variant alpha, mRNA. SERPINB4 exonic NM 002974Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 394 member4 (SERPINB4), mRNA. FLJ26850 intronic NR 027257 Homo sapiens FLJ26850protein (FLJ26850), non-coding RNA. 395 FPR2 exonic NM 001005738 Homosapiens formyl peptide receptor 2 (FPR2), transcript variant 396 2,mRNA. FPR2 exonic NM 001462 Homo sapiens formyl peptide receptor 2(FPR2), transcript variant 397 1, mRNA. FPR3 exonic NM 002030 Homosapiens formyl peptide receptor 3 (FPR3), mRNA. 398 ZNF577 exonic NR024181 Homo sapiens zinc finger protein 577 (ZNF577), transcript variant399 3, non-coding RNA. ZNF577 exonic NM 001135590 Homo sapiens zincfinger protein 577 (ZNF577), transcript variant 400 2, mRNA. ZNF577exonic NM 032679 Homo sapiens zinc finger protein 577 (ZNF577),transcript variant 401 1, mRNA. ZNF649 exonic NM 023074 Homo sapienszinc finger protein 649 (ZNF649), mRNA. 402 ZNF613 exonic NM 001031721Homo sapiens zinc finger protein 613 (ZNF613), transcript variant 403 1,mRNA. ZNF613 exonic NM 024840 Homo sapiens zinc finger protein 613(ZNF613), transcript variant 404 2, mRNA. ZNF350 exonic NM 021632 Homosapiens zinc finger protein 350 (ZNF350), mRNA. 405 ZNF615 exonic NM001199324 Homo sapiens zinc finger protein 615 (ZNF615), transcriptvariant 406 1, mRNA. ZNF615 exonic NM 198480 Homo sapiens zinc fingerprotein 615 (ZNF615), transcript variant 407 2, mRNA. ZNF614 exonic NM025040 Homo sapiens zinc finger protein 614 (ZNF614), mRNA. 408 ZNF432exonic NM 014650 Homo sapiens zinc finger protein 432 (ZNF432), mRNA.409 ZNF841 exonic NM 001136499 Homo sapiens zinc finger protein 841(ZNF841), mRNA. 410 NLRP12 exonic NM 001277126 Homo sapiens NLR family,pyrin domain containing 12 (NLRP12), 411 transcript variant 3, mRNA.NLRP12 exonic NM 001277129 Homo sapiens NLR family, pyrin domaincontaining 12 (NLRP12), 412 transcript variant 4, mRNA. NLRP12 exonic NM144687 Homo sapiens NLR family, pyrin domain containing 12 (NLRP12), 413transcript variant 2, mRNA. VSTM1 intronic NM 198481 Homo sapiens V-setand transmembrane domain containing 1 414 (VSTM1), mRNA. SNX5 exonic NM014426 Homo sapiens sorting nexin 5 (SNX5), transcript variant 2, mRNA.415 SNX5 exonic NM 152227 Homo sapiens sorting nexin 5 (SNX5),transcript variant 1, mRNA. 416 SNORD17 exonic NR 003045 Homo sapienssmall nucleolar RNA, C/D box 17 (SNORD17), 417 small nucleolar RNA.MGME1 exonic NM 052865 Homo sapiens mitochondrial genome maintenanceexonuclease 1 418 (MGME1), mRNA. OVOL2 exonic NM 021220 Homo sapiensovo-like 2 (Drosophila) (OVOL2), mRNA. 419 ADA intronic NM 000022 Homosapiens adenosine deaminase (ADA), mRNA. 420 NRIP1 exonic NM 003489 Homosapiens nuclear receptor interacting protein 1 (NRIP1), 421 mRNA. BACH1exonic NR 027655 Homo sapiens BTB and CNC homology 1, basic leucinezipper 422 transcription factor 1 (BACH1), transcript variant 3,non-coding RNA. BACH1 intronic NM 001186 Homo sapiens BTB and CNChomology 1, basic leucine zipper 423 transcription factor 1 (BACH1),transcript variant 2, mRNA. BACH1 intronic NM 206866 Homo sapiens BTBand CNC homology 1, basic leucine zipper 424 transcription factor 1(BACH1), transcript variant 1, mRNA. TRPM2 exonic NM 003307 Homo sapienstransient receptor potential cation channel, subfamily 425 M, member 2(TRPM2), transcript variant 1, mRNA. TRPM2 exonic NR 038257 Homo sapienstransient receptor potential cation channel, subfamily 426 M, member 2(TRPM2), transcript variant 2, non-coding RNA. ADARB1 intronic NM 001112Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 427transcript variant 1, mRNA. ADARB1 intronic NM 001160230 Homo sapiensadenosine deaminase, RNA-specific, B1 (ADARB1), 428 transcript variant7, mRNA. ADARB1 intronic NM 015833 Homo sapiens adenosine deaminase,RNA-specific, B1 (ADARB1), 429 transcript variant 2, mRNA. ADARB1intronic NM 015834 Homo sapiens adenosine deaminase, RNA-specific, B1(ADARB1), 430 transcript variant 3, mRNA. ADARB1 intronic NR 027672 Homosapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 431 transcriptvariant 5, non-coding RNA. ADARB1 intronic NR 027673 Homo sapiensadenosine deaminase, RNA-specific, B1 (ADARB1), 432 transcript variant4, non-coding RNA. ADARB1 intronic NR 027674 Homo sapiens adenosinedeaminase, RNA-specific, B1 (ADARB1), 433 transcript variant 6,non-coding RNA. ADARB1 intronic NR 073200 Homo sapiens adenosinedeaminase, RNA-specific, B1 (ADARB1), 434 transcript variant 8,non-coding RNA. APOBEC3A exonic NM 001270406 Homo sapiens apolipoproteinB mRNA editing enzyme, catalytic 435 polypeptide-like 3A (APOBEC3A),transcript variant 3, mRNA. APOBEC3A exonic NM 145699 Homo sapiensapolipoprotein B mRNA editing enzyme, catalytic 436 polypeptide-like 3A(APOBEC3A), transcript variant 1, mRNA. APOBEC3A intronic NM 001193289Homo sapiens APOBEC3A and APOBEC3B deletion hybrid 437 B (APOBEC3A B),mRNA. APOBEC3B exonic NM 001270411 Homo sapiens apolipoprotein B mRNAediting enzyme, catalytic 438 polypeptide-like 3B (APOBEC3B), transcriptvariant 2, mRNA. APOBEC3B exonic NM 004900 Homo sapiens apolipoprotein BmRNA editing enzyme, catalytic 439 polypeptide-like 3B (APOBEC3B),transcript variant 1, mRNA. MKL1 intronic NM 020831 Homo sapiensmegakaryoblastic leukemia (translocation) 1 440 (MKL1), mRNA. TNFRSF13Cexonic NM 052945 Homo sapiens tumor necrosis factor receptorsuperfamily, member 441 13C (TNFRSF13C), mRNA. CENPM exonic NM 001110215Homo sapiens centromere protein M (CENPM), transcript variant 442 3,mRNA. CENPM exonic NM 001002876 Homo sapiens centromere protein M(CENPM), transcript variant 443 2, mRNA. CENPM exonic NM 024053 Homosapiens centromere protein M (CENPM), transcript variant 444 1, mRNA.PPP2R3B intronic NM 013239 Homo sapiens protein phosphatase 2,regulatory subunit B″, beta 445 (PPP2R3B), mRNA. VCX exonic NM 013452Homo sapiens variable charge, X-linked (VCX), mRNA. 446 PNPLA4 exonic NM004650 Homo sapiens patatin-like phospholipase domain containing 4 447(PNPLA4), transcript variant 1, mRNA. PNPLA4 exonic NM 001142389 Homosapiens patatin-like phospholipase domain containing 4 448 (PNPLA4),transcript variant 2, mRNA. PNPLA4 exonic NM 001172672 Homo sapienspatatin-like phospholipase domain containing 4 449 (PNPLA4), transcriptvariant 3, mRNA. MIR651 exonic NR 030380 Homo sapiens microRNA 651(MIR651), microRNA. 450 JPX intronic NR 024582 Homo sapiens JPXtranscript, XIST activator (non-protein coding) 451 (JPX), non-codingRNA. GRIA3 intronic NM 000828 Homo sapiens glutamate receptor,ionotropic, AMPA 3 (GRIA3), 452 transcript variant 2, mRNA. GRIA3intronic NM 007325 Homo sapiens glutamate receptor, ionotropic, AMPA 3(GRIA3), 453 transcript variant 1, mRNA. GRIA3 intronic NM 001256743Homo sapiens glutamate receptor, ionotropic, AMPA 3 (GRIA3), 454transcript variant 3, mRNA. HMGB3 exonic NM 005342 Homo sapiens highmobility group box 3 (HMGB3), mRNA. 455

For all genes listed in Table 2 (namely, those relevant toCNV-subregions of interest), Table 4 represents a non-redundant list.

TABLE 5 The set of SNVs reported in Tables 7-10, 14, or 15 that werefound in the 70 PML cases in this study for which WES data weregenerated. Chromosome Position hg19 REF ALT SEQ ID  1 9777599 C G 1000 1 12172008 T C 1001  1 24486004 G T 1002  1 33476435 C A 1003  133478900 T A 1004  1 33487007 C T 1005  1 36932047 C T 1006  1 36933715A G 1007  1 42047208 C G 1008  1 59248085 G C 1009  1 59248339 T C 1010 1 92941660 C T 1011  1 92946625 G C 1012  1 92946625 G C 1013  1150053494 C T 1014  1 155317682 C T 1015  1 155449630 T G 1016  1155450331 C T 1017  1 182554557 C T 1018  1 198717250 T G 1019  1198717272 A T 1020  1 206945738 C T 1021  1 207641950 C T 1022  1235840495 G T 1023  1 235897907 C T 1024  1 235909815 A T 1025  224431184 C T 1026  2 24432937 C T 1027  2 24435599 G A 1028  2 47205921C T 1029  2 47273468 A G 1030  2 47277182 T C 1031  2 55910961 T C 1032 2 71337203 C T 1033  2 98351032 C G 1034  2 98351066 C T 1035  298351081 C T 1036  2 113589000 C T 1037  2 163124051 C T 1038  2163133194 T C 1039  2 163134203 G T 1040  2 163136505 C G 1041  2163139025 C T 1042  2 163139085 A T 1043  2 163144899 G A 1044  2163174327 C A 1045  2 163174328 T G 1046  2 219942026 T A 1047  2220023045 C T 1048  2 230231632 C T 1049  2 230450646 T A 1050  338181899 G T 1051  3 39323163 A C 1052  3 53213691 G C 1053  3 53221390T C 1054  3 121415370 T C 1055  3 128204761 C T 1056  3 128205808 C T1057  3 142272098 A G 1058  3 142274880 G C 1059  3 142281353 C G 1060 3 142286928 C T 1061  3 196199032 A T 1062  3 196199204 G T 1063  3196210704 G A 1064  3 196210764 T C 1065  3 196214320 C T 1066  427019452 C T 1067  4 27024170 A G 1068  4 103522068 A G 1069  4103522150 G A 1070  4 103528328 C T 1071  4 151199080 G A 1072  4151520216 G A 1073  4 187003729 C G 1074  4 187004074 C T 1075  4187005854 A C 1076  5 67591018 A C 1077  5 77311370 C T 1078  5 77311370C T 1079  5 77334964 T C 1080  5 77334964 T C 1081  5 77335015 G T 1082 5 77335015 G T 1083  5 77437092 G C 1084  5 77437092 G C 1085  578596018 G C 1086  5 138856923 C T 1087  5 156593120 C T 1088  5169081453 G C 1089  6 3077139 T C 1090  6 12121113 C T 1091  6 12122102T G 1092  6 12123538 G T 1093  6 12124215 C T 1094  6 12125232 C T 1095 6 12162068 C T 1096  6 12163657 C T 1097  6 31928306 A G 1098  631935750 G A 1099  6 31936679 C T 1100  6 32797809 C T 1101  6 32810794T A 1102  6 32811752 C T 1103  6 51483961 T C 1104  6 51484077 G C 1105 6 51491885 G A 1106  6 51497503 C A 1107  6 51524339 C G 1108  651524409 G T 1109  6 51612746 G A 1110  6 51712759 T C 1111  6 51747943T A 1112  6 51798908 C T 1113  6 52101833 C T 1114  6 83884161 C G 1115 6 143081232 T C 1116  6 143092151 T C 1117  6 143092673 G A 1118  6144508353 G A 1119  6 144508563 G A 1120  7 2959240 C T 1121  7 2962933C T 1122  7 2983958 T C 1123  8 39840234 A G 1124  8 39862881 C T 1125 8 39862893 T A 1126  8 42176189 G A 1127  8 48690299 A G 1128  848773526 T C 1129  8 48798507 T C 1130  8 48826575 C G 1131  8 61654298T A 1132  8 61732632 A G 1133  8 61757805 C T 1134  8 61769428 A G 1135 8 61777914 C G 1136  8 61777922 C G 1137  8 90990521 T C 1138  8100205255 G A 1139  8 100791158 G A 1140  8 100865941 G A 1141  8145154222 G A 1142  8 145154222 G A 1143  8 145154257 C G 1144  8145154824 A C 1145  9 286491 G A 1146  9 286593 C A 1147  9 304628 G A1148  9 312134 G A 1149  9 328047 T A 1150  9 334277 G A 1151  9 368128C T 1152  9 399233 A G 1153  9 446401 A G 1154  9 711359 C T 1155  9713132 G T 1156  9 32526077 C T 1157  9 32526077 C T 1158  9 120466814 AG 1159  9 120475302 A G 1160  9 120475602 C T 1161  9 120476568 A G 1162 9 120476816 C T 1163 10 1060218 G A 1164 10 14974905 T C 1165 1014976727 G C 1166 10 14977469 C A, T 1167 10 72358167 G A 1168 1076602923 G T 1169 10 76748831 C T 1170 10 89720659 G T 1171 10 90771767G A 1172 10 116045796 G A 1173 11 4104626 C A 1174 11 4112582 C T 117511 9598696 G A 1176 11 9608330 G A 1177 11 36595321 C T 1178 11 36596528G C 1179 11 36596863 C T 1180 11 36597513 G A 1181 11 36614561 G T 118211 36615033 C T 1183 11 67814983 G A 1184 11 67818269 G A 1185 1176954833 G A 1186 11 76979511 A G 1187 11 108117787 C T 1188 11108119823 T C 1189 11 108123551 C T 1190 11 108138003 T C 1191 11108143456 C G 1192 11 108175462 G A 1193 11 108181014 A G 1194 11108186610 G A 1195 11 108186631 A G 1196 11 108198384 C G 1197 11108202772 G T 1198 12 12673965 G A 1199 12 12870798 G A 1200 12 44166753A G 1201 12 44167821 A T 1202 12 64878241 G A 1203 12 64879775 C T 120412 88900891 C A 1205 12 93196332 C T 1206 12 93205148 T G 1207 12112583447 A C 1208 12 122064788 G GT 1209 12 133201381 T A 1210 12133202816 C T 1211 12 133209020 G C 1212 12 133220526 T C 1213 12133220544 C T 1214 12 133237658 T G 1215 12 133245026 G A 1216 12133252406 C A 1217 12 133253971 C T 1218 12 133253995 G A 1219 1347466549 T C 1220 13 108861092 G T 1221 13 108863591 G A 1222 1421992397 T C 1223 14 21993359 G A 1224 14 22004996 G T 1225 14 24805463G T 1226 14 24806303 G A 1227 14 61924007 C G 1228 14 103369593 G A 122915 41011016 G A 1230 15 68378781 A C 1231 15 77329479 C T 1232 1591306241 G A 1233 15 91310209 A G 1234 15 91326099 C T 1235 15 91328219G T 1236 15 91328310 A G 1237 15 91341543 A C 1238 16 1498408 G A 123916 1510535 C T 1240 16 1524855 C G 1241 16 7568296 C T 1242 16 7703891 AG 1243 16 7714909 C T 1244 16 7759119 G A 1245 16 7759496 C T 1246 1624124365 A G 1247 16 27460020 G A 1248 16 30133233 T C 1249 16 30134529A C 1250 16 50733536 T C 1251 16 50741791 C T 1252 16 50741791 C T 125316 50744688 A G 1254 16 50745021 C T 1255 16 50753867 G T 1256 1670503095 A G 1257 16 81819605 C T 1258 16 81902826 C T 1259 16 81904539C T 1260 16 81939089 T C 1261 16 81942028 C G 1262 16 81942175 A G 126316 81946278 A G 1264 16 81960772 C A 1265 17 7577069 C T 1266 1716852187 A G 1267 17 77926526 C T 1268 18 43445580 C T 1269 18 43445601T G 1270 18 43456296 C T 1271 18 43458306 G A 1272 18 43460105 C A 127318 43464763 C T 1274 18 43479473 T C 1275 18 43488030 T C 1276 1843496370 G A 1277 18 43496539 G A 1278 18 43497710 A G 1279 18 43523240C T 1280 18 43529551 C T 1281 18 43531186 C T 1282 18 44392443 T C 128318 48584504 C T 1284 18 56401523 C T 1285 18 60036429 G A 1286 1860052034 A C 1287 19 4817657 C T 1288 19 4817852 G A 1289 19 7705818 C T1290 19 7712287 G C 1291 19 48631258 G A 1292 19 48639022 T C 1293 203843027 C A 1294 20 3846397 C T 1295 20 31383307 G A 1296 20 31384614 GT 1297 20 62305450 C T 1298 20 62309621 T C 1299 20 62326964 C G 1300 2116338814 T C 1301 21 16339852 T C 1302 21 30698953 T G 1303 21 34809232C T 1304 21 45786650 C T 1305 21 45795833 G T 1306 21 45795877 G T 130721 45811411 G T 1308 21 45811438 C T 1309 21 45815307 T C 1310 2145815331 G A 1311 21 45815343 A G 1312 21 45815425 C G 1313 21 45820196C T 1314 21 45826486 G A 1315 21 45826616 C T 1316 21 45838333 C T 131721 45844780 C T 1318 21 45845528 G A 1319 21 45845661 A G 1320 2145845699 G A 1321 21 45855099 C T 1322 22 21235389 A G 1323 22 23915583T C 1324 22 23915745 G A 1325 22 23917192 G T 1326 22 36661354 C T 1327X 24759574 G T 1328 X 24759574 G T 1329

Table 5 lists, in order of genomic coordinates, all single nucleotidevariants (SNVs) that are relevant to the present study, whether ascase-level solutions (Tables 7, 8) or potential solutions (Tables 9,10), or at the level of variant burden analysis (Tables 14, 15). Allgenome coordinates are based on hg19.

TABLE 6 Non-redundant list of 419 genes involved in the immune systemand/or linked to PML via a CNV RefSeq Gene Gene Disease Gene NumberSymbol Model Source Source Annotation (GN) ACADM AR Public MySql 157 dbACKR1 AD Public MySql 158 db ACP5 AR Public PMID: 26052098, 27260006,27821552 159 db ADAR AD AR Public PMID: 26052098, 27260006, 27821552 160db ADARB1 unknown PBio PMID: 16227093, 17376196, 19482597, 20220309,21682836, 2 21809195, 22001568, 22085847, 22113393, 24586166, 24725957,24760760, 25826567 ADK AR PBio PMID: 17205396, 23592612, 25654762,25720338, 25979489, 161 26341819, 26642971 AGBL4 unknown PBio PMID:17244818, 21074048, 23085998, 25416787, 25332286, 3 26502776 AICDA AD ARPublic MySql; PMID: 23765059 162 db AK2 AR Public PMID: 19043417,19782549, 20008220, 23765059, 24135998, 163 db 24753205, 26454313 ALG12AR Public MySql 164 db ALPL AD AR PBio PMID: 18821074, 20049532,20977932, 21191615, 21289095, 165 23091474, 23454488, 23860646,26219705, 26219711, 26219717 AP3B1 AR Public MySql; PMID: 11590544,19782549, 24302998, 24753205, 166 db 24916509, 25980904, 27889060 AP3B2AR Public PMID: 26377319, 27889060 167 db AP3D1 AR Public PMID:26744459, 27889060 168 db APOBEC3A unknown PBio PMID: 16720547,17303427, 20062055, 20615867, 22896697, 4 23344558, 23640892, 25262471,25576866, 26416327, 26489798, 26678087 APOBEC3B unknown PBio PMID:16720547, 17303427, 20062055, 20615867, 22896697, 6 23344558, 23640892,25262471, 25576866, 26416327, 26489798, 26678087 APOL1 associationPublic PMID: 27042682 169 db ARHGEF7 unknown PBio PMID: 11160719,16983070, 18378701, 19861492, 25284783, 8 25500533 ASH1L unknown PBioPMID: 17923682, 17981149, 22541069, 24012418, 24244179, 170 25866973,26002201, 27154821, 27229316, 27434206 ASTN2 unknown PBio PMID: 92223091, 8602532, 20573900, 24357807, 24381304, 25146927, 25410587,26514622, 26586575 ATL2 unknown PBio PMID: 18270207, 19665976, 25773277171 ATM AR Public MySql; PMID: 19903823, 20301790, 23765059, 24799566,172 db 25692705, 27042682, 27484032, 27884168, 27895165 ATR AD AR PublicPMID: 17564965, 17151099, 19903823, 20506465, 173 db 21615334, 24799566,25910481 AUH AR PBio PMID: 12434311, 12655555, 17130438, 20855850,25280001, 10 25597510 BACH1 unknown PBio PMID: 15068237, 18555605,22024395, 22791292, 23456643, 11 23562577, 24752012, 25344725, 25391381,24752012, 26045540, 26894991 BACH2 unknown PBio PMID: 17262715,17991429, 18769450, 22791292, 23728300, 174 24367030, 24608439,24681888, 24694524, 25123280, 25344725, 25665584, 25686607, 26444573,26620562, 26731475, 26894991, 26981933 BCL10 AR Public MySql 176 dbBDKRB2 unknown PBio PMID: 7787759, 18930543, 22047990, 22095814,24925394 12 BLM AR PBio PMID: 15137905, 15493327, 17210642, 17321898,19109166, 177 19709744, 2032252, 23572515, 24606147 BLNK AR Public PMID:23765059 178 db BLOC1S6 AR Public MySql 179 db BMPR2 AD PBio PMID:15877825, 19191909, 23733693, 24334027 13 C11orf65 unknown Public MySql181 db C1QA AR Public PMID: 27821552 182 db C1QB AR Public PMID:27821552 183 db C1QC AR Public PMID: 27821552 184 db C5AR1 unknown PBioPMID: 1847994, 22964232, 25041699, 25174320, 25455139, 185 25539817,25769922, 26059553, 26283482, 26537334 CAPZB unknown PBio PMID:99354614, 19806181, 22493691, 22706086, 22710966, 186 22918941,23178720, 26758871 CARD11 AD AR Public MySql; PMID: 23765059, 25645939,26525107 187 db CARD9 AR Public PMID: 27222657 188 db CASP8 AR PublicPMID: 22365665, 26454313, 27873163, 27999438 189 db CCL11 AD PublicMySql 190 db CCL2 association Public MySql 191 db CCL5 associationPublic MySql 192 db CCR2 association Public MySql 193 db CCR5association Public MySql 194 db CD180 unknown PBio PMID: 9763566,10880523, 21918197, 21959264, 22484241, 195 23103284, 23483427,24019553, 25749095, 26371254, 26384474, 26482097, 26555723, 26371254CD19 AR Public MySql; PMID: 23765059, 26453379 196 db CD209 associationPublic MySql 197 db CD247 AR Public PMID: 26454313 198 db CD27 AR PublicMySql; PMID: 23765059 199 db CD27-AS1 unknown Public MySql 200 dbCD300LF unknown PBio PMID: 15184070, 15549731, 17202342, 18688020,19592130, 23 22288587, 23072861, 23293083, 24035150 CD34 unknown PublicPMID: 27042682 201 db CD3D AR Public PMID: 23765059, 26454313 202 dbCD3E AR Public PMID: 23765059, 26454313 203 db CD3G AR Public PMID:23765059, 26454313 204 db CD40 AR Public MySql; PMID: 23765059, 26453379205 db CD55 unknown PBio PMID: 12417446, 1385527, 16406700, 16503113,17678954, 207 18424707, 19660813, 21143144, 22795896, 24588829,24639397, 25156074, 25954012, 26423932 CD59 AR Public MySql 208 db CD79AAR Public PMID: 23765059 209 db CD79B AR Public PMID: 23765059 210 dbCD81 AR Public MySql 211 db CD8A AR Public PMID: 26454313 212 db CDCA7AR Public PMID: 26216346 213 db CDKN1B AD PBio PMID: 10799578, 10825149,10916090, 11123298, 11123306, 24 115557280, 16410832, 17273559,20854895, 21078910, 22454463, 24317118, 25213837 CEBPB unknown PublicPMID: 27042682 214 db CENPM unknown PBio PMID: 15183305, 16391015,19711193, 25006165 25 CHD7 AD Public PMID: 18505430, 18976358, 26454313,27484032 215 db CHEK1 unknown Public PMID: 19903823, 27042682 216 dbCIITA AR Public PMID: 23765059, 26454313, 27484032 217 db CLCN7 AD PMID:21107136, 25992615 218 COG4 AR PBio PMID: 18086915, 18256213, 20065092,20143049, 21421995, 26 23462996, 23865579, 24784932, 26125015 COG6 ARPublic MySql 219 db COMMD6 unknown PBio PMID: 14685242, 15799966,16573520, 20126548, 25355947, 27 27441653 CORO1A AR Public PMID:23887241, 26454313 220 db CR2 AR Public MySql 221 db CRADD AR PBio PMID:11573962, 21242994, 22323537, 24958727, 26190521, 28 27135977 CRTC3unknown PBio PMID: 15466468, 2032252, 21536665, 23033494, 23241891, 22225114223, 25316186, 25351958, 26937622 CSF3R AR Public PMID: 24753537,26324699, 27789332 223 db CTLA4 AD Public PMID: 18219311, 25213377,25329329 224 db CTPS1 AR Public MySql 225 db CTSC AR Public PMID:27222657 226 db CX3CR1 association Public MySql 227 db CXCL12association Public MySql 228 db CXCL9 unknown Public PMID: 27042682 229CXCR1 association Public MySql 230 db CXCR4 AD Public PMID: 19782549,19950235, 23765059, 24753205, 25645939, 231 db 28009639 CXorf40A unknownPBio PMID: 15541360, 24916366, 26881174 232 CYBB XLR Public PMID:27222657 233 db CYP2S1 unknown PBio PMID: 15681441, 23933117 234 DCLRE1CAR Public PMID: 26454313, 26476407, 27484032 235 db DDX1 unknown PublicPMID: 27042682 236 db DDX58 AD Public PMID: 23592984, 25692705,25794939, 26052098, 26748340, 237 db 26848516, 26987611, 27260006,27821552 DHX58 association Public PMID: 25794939, 26748340, 26848516 238db DKC1 XLR Public MySql; PMID: 23765059 239 db DNER unknown PBio PMID:15965470, 16298139, 16997755, 17765022, 18474614, 31 20058045, 20367751,22447725, 23041955, 23328254, 24248099, 24935874, 26869529 DOCK2 ARPublic MySql 241 db DSC1 unknown PBio PMID: 16048752, 20222919,22692770, 24460202, 24680560, 243 25078507, 25244249, 26043694, 26758100DUSP16 unknown PBio PMID: 15284860, 21613215, 24311790, 25716993,26381291, 32 27162525 ECRP unknown PBio PMID: 9826755, 12855582,25271100, 26184157 33 EDIL3 unknown PBio PMID: 22601780, 23518061,24060278, 24504014, 25385367, 34 26038125 EEA1 unknown PBio PMID:16670179, 22591512, 24491918, 24561067, 26478006, 35 26909655, 27077111EGR1 unknown PBio PMID: 15308739, 19050264, 19812322, 20414733,21368226, 244 21622185, 22554935, 25613134, 26052046, 26980486,11910893, 14647476, 18203138, 24627779, 25368162, 27192563 EHF unknownPBio PMID: 16380452, 17027647, 19801549, 20879862, 21617703, 3624219556, 25217163 ELANE AD Public PMID: 20008220, 24145314, 27222657245 db EMB unknown PBio PMID: 8432389, 15917240, 18209069, 19164284,25773908 37 EPG5 AR Public MySql; PMID: 21965116, 23222957, 23838600,26917586, 246 db 26927810, 27588602 ETF1 unknown PBio PMID: 20418372,25606970, 26384426, 26833392, 27387891 247 ETV6 AD PBio PMID: 19264918,20350664, 21714648, 22438058, 25581430, 38 25807284, 26718572, 27365488F9 XLR Public MySql 248 db FAS AD Public PMID: 27222657 249 db FASLG ADPublic PMID: 27222657 250 db FCGR2A AD AR Public MySql 251 db FCGR3A ARPublic MySql 252 db FCN3 AR Public MySql 253 db FEZ1 unknown PublicPMID: 27042682 254 db FHL2 unknown PBio PMID: 16389449, 20592280,22417706, 22633286, 23212909 39 FOS unknown Public PMID: 27042682 255 dbFOXH1 unknown Public PMID: 27042682 256 db FOXN1 AR Public MySql 257 dbFOXP3 XLR Public PMID: 26454313 258 db FPR1 unknown PBio PMID: 8994115,10229829, 10611407, 17084101, 22934745, 259 23230437, 25605714,25826286, 26101324, 26701131, 27034344, 27100350, 27131862, 27154726FPR2 unknown PBio PMID: 8994115, 10229829, 10611407, 17084101, 22934745,41 23230437, 25605714, 25826286, 26101324, 26701131, 27034344, 27100350,27131862, 27154726 FPR3 unknown PBio PMID: 8994115, 10229829, 10611407,17084101, 22934745, 42 23230437, 25605714, 25826286, 26101324, 26701131,27034344, 27100350, 27131862, 27154726 FUK unknown PBio PMID: 11753075,12651883, 15774760, 19394435, 19647987, 43 20363321, 22134107, 22203233,22276660, 22461019, 24239607 G6PC3 AR Public PMID: 20008220, 24145314,25879134, 26479985 260 db GATA2 AD Public PMID: 23765059, 23887241 261db GDA unknown PBio PMID: 10595517, 18600524, 20826431, 23838888,24834013 44 GDPD4 unknown PBio PMID: 24373430, 24977479, 24977485,24977489, 25528375, 45 25596343 GFI1 AD Public PMID: 20008220, 24145314262 db GOLGB1 unknown PBio PMID: 17475246, 21217069, 22034594, 23555793,24046448 263 GPATCH2 unknown PBio PMID: 19432882, 25353171, 25376275 46GPC5 unknown PBio PMID: 24130709, 24943672, 25354479, 26224662, 2634947747 GPRC5A unknown PBio PMID: 19593893, 20959490, 22239913, 25621293,25714996, 264 26165721 GRAP2 unknown Public PMID: 25452106, 25636200,26246585 265 db GRIA3 XLR PBio PMID: 10441169, 12682273, 17202328,18590483, 25904555, 51 26648591 GTPBP4 unknown PBio PMID: 17785438,26015807 52 HAX1 AR Public PMID: 20008220, 24145314 266 db HCN1 AD PBioPMID: 9405696, 9630217, 9634236, 9921901, 11133998, 53 23042740,23077068, 23319474, 24403084, 24747641, 24756635, 25580535, 26578877HELLS AR Public PMID: 26216346 267 db HEXA AR PBio PMID: 20301397,21997228, 23727835, 24445368 54 HIVEP1 association Public MySql; PMID20226436, 26117544 268 db HIVEP2 AD Public MySql; PMID: 21475200,21936769, 23389689, 24366360, 269 db 26153216, 26483320, 27003583 HIVEP3unknown Public MySql 270 db HK2 unknown PBio PMID: 2749583, 4265132,19519254, 2496891, 23874603, 55 25525876, 25602755 HMGB3 unknown PBioPMID: 12714519, 15259015, 15358624, 16945912, 22014684, 56 23994280,26553261 HNRNPLL unknown PBio PMID: 18669861, 18719244, 19100700,20505149, 22073166, 271 23934048, 24476532, 25825742 HP unknown PBioPMID: 16046400, 19380867, 19795414, 26445729 272 HPCAL1 unknown PBioPMID: 12445467, 24699524, 25519916, 26659654, 26729710 273 HPR unknownPBio PMID: 16046400, 19380867, 19795414, 26445729 57 HTR2A associationPublic PMID: 19204164, 24089568, 25078361, 26056932, 27003757, 274 db27042682 ICOS AR Public MySql; PMID: 19380800, 23765059, 27250108 275 dbIDI1 unknown PBio PMID: 14629038, 17202134, 19454010, 20955688,22579571, 276 23585482, 25950736 IDI2 unknown PBio PMID: 14629038,17202134, 19454010, 20955688, 22579571, 59 23585482, 25950736 IDI2-AS1unknown PBio See IDI2 IDO2 unknown PBio PMID: 18219311, 18364004,19487973, 19799997, 20197554, 61 20484729, 20693847, 21084489, 21406395,21990421, 22754762, 24391212, 24402311, 24844751, 25477879, 25478733,25541686, 25949913, 26308414, 27183624 IFIH1 AD Public PMID: 21156324,24686847, 24995871, 25794939, 26052098, 277 db 26748340, 27260006,27821552 IFNAR1 association Public PMID: 27821552 278 db IFNAR2 ARPublic PMID: 26424569, 27821552 279 db IFNG association Public MySql 280db IFNGR1 AD AR Public MySql 281 db IFNGR2 AD AR Public MySql; PMID:15356149, 23161749 282 db IFNLR1 unknown PBio PMID: 12469119, 12483210,15166220, 22386267, 22891284, 62 25634147, 25904743, 25941255 IGLL1 ARPublic PMID: 25502423 283 db IKBKB AD AR Public MySql; PMID: 17047224,17072332, 25764117, 25930993, 284 db 26117626, 26525107 IKBKG XLD XLRPublic MySql; PMID: 17047224, 21455173, 21455181, 23765059, 285 db25764117, 25886387, 25930993, 26117626, 26525107 IKZF1 AD Public PMID:26454313, 26981933 286 db IL10 AR Public PMID: 23887241 287 db IL10RA ARPublic PMID: 23887241 288 db IL10RB AR Public PMID: 23887241 289 dbIL12B AR Public MySql 290 db IL12RB1 AR Public MySql 291 db IL17F ADPublic PMID: 22284928, 23887241, 24240291, 24690400, 25890879, 292 db27144517 IL17RA AR Public PMID: 23887241 293 db IL1B AD Public PMID:15327898, 20543597, 24248593, 26525107, 27730320, 294 db 27873163,27999438 IL21 AR Public MySql 295 db IL21R AD AR Public PMID: 23765059,23887241 296 db IL2RA AR Public MySql 297 db IL2RG XLR Public PMID:23765059, 26454313, 27484032 298 db IL4R association Public MySql 299 dbIL7 unknown PBio PMID: 21508983, 22288682, 24507157, 24979548, 25130296,300 25214510, 25411246, 25734144, 26537673, 26675348, 26908786 IL7R ARPublic PMID: 301 db 26454313, 27484032 IRAK4 AD AR Public PMID:23766853, 25232776, 25344726, 25764117, 25886387, 302 db 25930993,26785681, 27845762 IRF3 AD Public PMID: 23388631, 26513235, 26748340 303db IRF7 AR Public MySql; PMID: 26748340 304 db IRF8 AD AR Public PMID:23887241 305 db IRGM association PBio PMID: 14707092, 17911638,22174682, 22722598, 23084913, 306 23335927 ISG15 AR Public MySql; PMID:26052098, 27260006, 27821552 307 db ITSN2 unknown PBio PMID: 11748279,15020715, 17696400, 17696407, 22558309, 309 22975684, 23986746,24097067, 24284073, 25797047, 26479042 JAGN1 AR Public PMID: 25129144310 db JAK3 AR Public PMID: 23765059, 26454313 311 db JMY unknown PBioPMID: 19287377, 20573979, 20574148, 20888769, 21965285, 312 23291261,25015719, 26223951, 26305109 JPX association PBio PMID: 21029862,23791181, 23943155 64 JUN unknown Public PMID: 16928756, 27042682 313 dbKANK1 association PBio PMID: 18458160, 20164854, 21685469, 24399197,25961457, 65 26656975 KAT6B AD PBio PMID: 17460191, 17694082, 22715153,25920810 66 KCTD7 AR PBio PMID: 17455289, 20301601, 21710140, 22606975,22638565, 67 22748208, 25060828, 27629772, 27742667 KITLG AD PublicPMID: 27042682 314 db LAMTOR2 AR Public MySql; PMID 19782549, 20008220,24753205 315 db LARP4B unknown PBio PMID: 20573744, 23815932, 25534202,26001795, 26501340, 69 26644407 LCP2 unknown Public PMID: 12874226,18219311, 19056831, 23494777, 26246585 317 db LIG1 AR Public MySql 318db LIG4 AR Public MySql 319 db LOC102724297 unknown Public MySql 320 dbLOC400710 unknown PBio ncRNA, limited gene information; see SNAR genefamily 321 (adjacent locus) LRBA AR Public MySql; PMID: 23765059,27873163, 27192563 322 db LYST AR Public PMID: 19302049, 19782549,20008220, 24753205, 24916509, 323 db 26454313, 27881733 MAGEA9 unknownPBio PMID: 15222021, 15900605, 21093980, 21791470, 25315972, 32425445503, 25755744 MAGEA9B unknown PBio PMID: 15222021, 15900605,21093980, 21791470, 25315972, 325 25445503, 25755744 MAGT1 XLR PublicPMID: 23887241, 27873163, 25504528 326 db MALL unknown PBio PMID:11294831, 19064697, 24101378, 24746959, 26109641, 72 26622604, 26641089,26772392, 27583248, 27846891 MALT1 AR Public MySql; PMID: 26525107 327db MAP3K2 unknown PBio PMID: 11032806, 11278622, 12138187, 14734742,16430878, 328 21333552, 2437584, 24847879, 25012295, 26056008 MAPK1unknown Public PMID: 14671106, 27042682 329 db MAPK3 unknown PublicPMID: 14671106, 27042682 330 db MAPK9 unknown PBio PMID: 15023353,23685277, 24673683, 25762148, 26141991 73 MAVS association Public PMID:23582325, 26513235, 26987611 331 db MCEE AR PBio PMID: 17846917,20301409, 21365456, 23726524, 24532006, 74 25763508, 26725562 MECP2 XLDXLR Public PMID: 27042682 332 db MEX3C unknown PBio PMID: 18779327,22357625, 22658931, 22863774, 22927639, 333 23140835, 23446422,23999169, 24706898, 24741071 MGAT5 unknown PBio PMID: 12417426,15585841, 18292539, 20089585, 20117844, 75 25768892, 26972830 MKL1 ARPBio PMID: 12944485, 22626970, 26098208, 26098211, 26221020, 8926241940, 26405212, 26224645, 26554816 MRE11A AR Public PMID: 23388631,23765059 334 db MS4A1 AR Public MySql; PMID: 23765059 335 db MSN unknownPBio PMID: 9070665, 10444190, 11777944, 12445265, 14758359, 33616368573, 17110458, 18025306, 18725395, 21486194, 23526587, 23613524,24250818, 24358210, 24760896, 25746045 MTHFD1 AR Both PMID: 26454313 337MYD88 AD AR Public PMID: 23766853, 25344726, 25764117, 25886387,25930993, 338 db 26371186, 27435819 NBN AD AR Public MySql; PMID:23765059 339 db NFIC unknown PBio PMID: 11559801, 15327898, 16928756,18474555, 19058033, 340 22205750 NFIL3 unknown PBio PMID: 20080759,20697558, 22075207, 23453631, 24070385, 92 24277151, 24280221, 24442434,24909887, 25092873, 25113970, 25310240, 25611557, 25614966, 25801035,25993115, 26153760, 26379372, 26806130, 26880402 NFKB1 AD Public PMID:22081022, 26279205 341 db NFKB2 AD Public MySql; PMID: 25764117 342 dbNFKBIA AD Public MySql; PMID: 23765059, 25645939, 25764117 343 db NHEJ1AR Public MySql; PMID: 23765059 344 db NLRP12 AD PBio PMID: 17947705,18230725, 20861596, 21978668, 23318142, 93 23970817, 24282415, 24347638,25249449, 25620184, 25902475, 26083549, 26343520, 26386126, 26521018NLRP3 AD Public PMID: 16724804, 19302049, 23592984, 26848516, 27999438345 NOD2 AD Public PMID: 16724804, 19302049, 23584365, 26509073,26848516, 346 db 26953272 NQO2 unknown PBio PMID: 16253210, 16905546,17720881, 18552348, 26046590 94 NRIP1 unknown PBio PMID: 18267075,23241901, 24969109, 25066731, 25697398, 95 25879677, 26937622 ORAI1 ADAR Public PMID: 19075015, 20004786, 21790973, 22144678, 23765059, 347 db26454313, 26469693 OSTM1 AR Public PMID: 16813530, 19507210, 21107136,23685543 348 db OVOL2 AD PBio PMID: 16423343, 25267199, 26619963,26749309 98 PDE3B unknown PBio PMID: 17220874, 23276671, 25816736,26203135, 26297880, 99 26374610 PDGFRA association PBio PMID: 12660384,18634583, 18701889, 19246520, 19839938, 100 20032375, 20569695,21123584, 21975205, 22449623, 22523564, 23771592, 25319708, 25940087PDSS2 AR PBio PMID: 17186472, 18437205, 18784258, 21567994, 21871565,101 21983691, 23150520 PGM3 AR Public MySql; PMID: 25502423 349 dbPHACTR4 unknown PBio PMID: 15107502, 17609112, 22215804, 22215812,22766235, 102 23076051, 23203801, 23319639, 24748504, 26850007 PIAS1unknown PBio PMID: 10805787, 10858346, 14644436, 15297606, 15311277, 10317065208, 17540171, 18056374, 19857525, 20966256, 22969086, 22982248,23299081, 24036127 PIAS2 unknown PBio PMID: 9724754, 11117529, 12077349,12764129, 14514699, 350 15582666, 16460827, 19549844, 21156324,21779164, 22210188, 22982248, 24344134, 25484205, 25434787, 26223632PIK3CD AD Both MySql; PMID: 24165795, 25133419, 25645939, 26437962, 10426453379, 27379089, 27426521, 27873163, 14647476, 27192563 PIK3R1 AD ARPublic PMID: 23765059, 23887241, 25645939, 26246585, 26453379, 351 db27076228, 14647476, 27192563 PKHD1 AR PBio PMID: 8178487, 15052665,17450421, 23423256, 24964219, 105 24984783, 25186187, 26502924 PLCG2 ADPublic PMID: 19056831, 23000145, 23765059, 23887241, 25452106, 352 db25636200, 25645939, 26246585, 27192563 PMS2 AR Public MySql; PMID:23765059 353 db PNPLA4 unknown PBio PMID: 22289388, 23741432, 26017929,26164793, 26713677, 107 26741492, 26968210 PNPT1 AR PBio PMID: 14563561,15492272, 16410805, 16687933, 17983748, 108 19580345, 23084291,23221631, 24143183, 24729470, 25457163 POLA1 XLR Public PMID: 27019227,27821552 355 db POLE AR Public MySql; PMID: 23230001, 23765059, 25948378356 db PPP2R3B unknown PBio PMID: 9847399, 10629059, 11593413, 18353419,20485545, 109 26683421 PRF1 AD AR Public PMID: 17311987, 19302049,21881043, 24916509, 25776844, 357 db 26454313, 26864340, 27391055 PRKCBunknown PBio PMID: 10872892, 15488737, 16935002, 17060474, 17395590, 11019907441, 21997316, 22994860, 23959874, 24550541, 25548371, 24550541,25808972, 26509731, 26510741 PRKCD AR Public MySql; PMID: 23319571,27250108, 27873163 358 db PRKCH unknown PBio PMID: 15327898, 16571806,18353419, 22114277, 22155788, 111 22892130, 23868949, 24705298,25617472, 25889880 PRKDC AD AR Public PMID: 12847277, 23722905,26454313, 26838362, 27980111 359 db PROC AD AR PBio PMID: 2437584,18751723, 21114396, 22447930, 24162617 360 PSMB8 AR Public PMID:26052098, 27260006, 27821552 361 db PSTPIP1 AD PBio PMID: 9488710,11313252, 12530983, 14707117, 16724804, 112 119290936, 19302049,24421327, 25040622, 25645939, 25814341, 26386126, 26919742 PTEN ADPublic PMID: 26246517, 27426521 362 db PTPN2 unknown PBio PMID:11909529, 12359225, 12847239, 19290937, 19825843, 113 19930043,20473312, 20564182, 20848498, 21220691, 22080861, 22080863, 22671594,24442435, 24445916, 24608439, 24849651, 24997008, 25548153, 25581833PTPRC AR Public PMID: 26454313 363 db PTPRN2 unknown PBio PMID: 9714834,10426369, 11086001, 11086294, 11793386, 114 15114673, 19361477,23595248, 24988487, 26141787, 26609326 PURA AD Public PMID: 27042682 364db RAB27A AR Public PMID: 19302049, 20008220, 21881043, 23810987 365 dbRAB37 unknown PBio PMID: 21805469, 22899725, 26931073, 27798165 115RAB7A AD PMID: 25992615, 27588602 366 RABGEF1 unknown PBio PMID:12505986, 15143060, 15235600, 16499958, 16533754, 367 16605131,17341663, 20829437, 22846990, 23552075, 24569883, 24957337, 25427001,26567216, 26588713, 27791468 RAC2 AD Public MySql 368 db RAD51 AD PublicPMID: 25310191, 27042682 369 db RAG2 AR Public PMID: 23765059, 23887241,26454313, 27808398 371 db RBCK1 AR Public MySql; PMID: 21455173,21455181, 23765059, 23969028, 372 db 24958845, 25764117, 25930993,26008899, 26525107, 27810922 RBFOX1 unknown PBio PMID: 23350840,24039908, 25043849, 26500751, 26687839 116 RCC1 unknown PBio PMID:1961752, 18442486, 19060893, 20347844, 23536659, 117 25452301, 26864624RFX5 AR Public PMID: 23765059, 26454313 373 db RFXANK AR Public PMID:23765059, 26454313 374 db RFXAP AR Public PMID: 23765059, 26454313 375db RGCC unknown PBio PMID: 19158077, 19652095, 23000427, 24973210,25770350, 118 26134570 RHOQ unknown PBio PMID: 10490598, 12456725,14734537, 16246732, 17016434, 119 19258391, 22916134, 24223996,24297911, 24663214, 24667291 RIPK1 association Public PMID: 21455173,27999438 376 db RIPK3 association Public PMID: 22365665, 27999438 377 dbRMRP AR Public MySql; PMID 19782549, 20008220, 24753205 378 db RNASE3unknown PBio PMID: 19515815, 26184157 120 RNASEH2A AR Public PMID:26052098, 27260006, 27821552 379 db RNASEH2B AR Public PMID: 26052098,27260006, 27821552 380 db RNASEH2C AR Public PMID: 26052098, 27260006,27821552 381 db RNASEL association Public PMID: 24995003, 27525044 382db RNF168 AR Public MySql; PMID: 23765059 383 db RNF31 AR Public PMID:21455173, 21455181, 23969028, 24958845, 26008899, 384 db 26525107,27810922 RNU4ATAC AR Public PMID: 27222657 385 db RPTOR unknown PBioPMID: 16959881, 22810227, 23349361, 23812589, 24287405, 123 24303063,24671993, 24948799, 26678875 RTEL1 AR Public MySql; PMID: 23329068,23765059, 24009516, 25607374, 386 db 26810774 RTEL1- unknown PublicMySql; PMID: 23329068, 23765059, 25607374 387 TNFRSF6B db SALL2 AR PBioPMID: 11734654, 15082782, 18818376, 19076363, 19131967, 388 21362508,21689070, 21791360, 22074632, 22978642, 23029531, 24040083, 24412933,24903482, 25360671, 25580951, 25608837, 26181197 SAMHD1 AR Public PMID:26052098, 27260006, 27821552 389 db SBDS AR Public PMID: 20008220,21062271, 27418648, 27658964 390 db SERPINB4 unknown PBio PMID:15203215, 19070595, 21857942, 22451727, 22808225, 124 24560885,24635038, 25111616, 25133778, 25213322 SERPINB6 AR PBio PMID: 14670919,20451170, 24172014, 24359430 125 SH2D1A XLR Public MySql; PMID:19302049, 23765059, 25744037 391 db SHARPIN unknown Public PMID:21455181, 22901541, 23969028, 24958845, 26525107, 392 db 26848516,27810922, 27892465 SKIV2L AR Public PMID: 27260006, 27821552 393 dbSLC17A5 AR PBio PMID: 14742248, 15006695, 15172005, 16575519, 18399798,127 20007460, 20951965, 21628664, 22778404, 23760462, 23889254,25494612, 25855729, 25879139 SLC37A4 AR Public PMID: 20008220, 20301489394 db SLC3A2 unknown PBio PMID: 22588539, 22624878, 23297381, 24491544,25002078, 126 26172215, 26439699, 26444422 SLC46A1 AR Public PMID:26454313 395 db SLC8A1 unknown PBio PMID: 23224883, 23224887, 23224890,23224891, 26045217, 396 26418956, 26775040, 26859825, 26924806 SMAD2unknown Public PMID: 27042682 397 db SMAD3 AD Public PMID: 27042682 398db SMAD4 AD Both PMID: 12202226, 14987161, 16800882, 19420158, 25637015,399 25705527, 26454313, 27042682 SNAP29 AR Public PMID: 15968592,21073448, 27588602 400 db SNAR-A1 unknown PBio PMID: 25327818, 25447144401 SNAR-A10 unknown PBio PMID: 25327818, 25447144 402 SNAR-A11 unknownPBio PMID: 25327818, 25447144 403 SNAR-A12 unknown PBio PMID: 25327818,25447144 404 SNAR-A13 unknown PBio PMID: 25327818, 25447144 405 SNAR-A14unknown PBio PMID: 25327818, 25447144 406 SNAR-A2 unknown PBio PMID:25327818, 25447144 407 SNAR-A3 unknown PBio PMID: 25327818, 25447144 408SNAR-A4 unknown PBio PMID: 25327818, 25447144 409 SNAR-A5 unknown PBioPMID: 25327818, 25447144 410 SNAR-A6 unknown PBio PMID: 25327818,25447144 411 SNAR-A7 unknown PBio PMID: 25327818, 25447144 412 SNAR-A8unknown PBio PMID: 25327818, 25447144 413 SNAR-A9 unknown PBio PMID:25327818, 25447144 414 SNAR-B1 unknown PBio PMID: 25327818, 25447144 415SNAR-B2 unknown PBio PMID: 25327818, 25447144 416 SNAR-C1 unknown PBioPMID: 25327818, 25447144 417 SNAR-C2 unknown PBio PMID: 25327818,25447144 418 SNAR-C3 unknown PBio PMID: 25327818, 25447144 419 SNAR-C4unknown PBio PMID: 25327818, 25447144 420 SNAR-C5 unknown PBio PMID:25327818, 25447144 421 SNAR-D unknown PBio PMID: 25327818, 25447144 422SNAR-E unknown PBio PMID: 25327818, 25447144 423 SNAR-F unknown PBioPMID: 25327818, 25447144 424 SNAR-G1 unknown PBio PMID: 25327818,25447144 425 SNAR-G2 unknown PBio PMID: 25327818, 25447144 426 SNAR-Hunknown PBio PMID: 25327818, 25447144 427 SNAR-I unknown PBio PMID:25327818, 25447144 428 SNCA AD PBio PMID: 12406186, 14648159, 16953112,19115126, 19432400, 429 19652146, 22209147, 23378275, 23771222,24586351, 24593806, 25092570, 25450953, 25522431, 25635231, 25866630,26087293, 26272943, 26342897, 26646749 SNHG3 unknown PBio PMID:22308462, 22843687, 26373735 128 SNX10 AR Public PMID: 22499339,23123320 430 SNX5 unknown PBio PMID: 10600472, 11128621, 14499622,15133132, 15561769, 130 16857196, 18596235, 21725319, 21903422,21943487, 23213485, 24820351, 26220253 SOCS2 unknown PBio PMID:19279332, 21403007, 22693634, 22795647, 23455506, 131 24400794,26216515, 26709655, 26765997, 27071013, 27158906, 27330188, 27338192SP110 AR Public MySql 431 db SP140 unknown Public MySql 432 db SPINK5 ARPublic PMID: 19683336, 26865388, 27222657, 27905021 433 db SQSTM1 AD ARPublic PMID: 19229298, 27715390 434 db SRSF1 unknown Public PMID:27042682 435 db ST8SIA5 unknown PBio PMID: 11089916, 15829700 133 STAT2AR Public PMID: 23391734, 26122121, 27821552 437 db STAT5B AR PublicMySql 439 db STIM1 AD AR Public PMID: 20004786, 21790973, 23765059,26454313, 26469693 440 db STIM2 unknown PBio PMID: 20004786, 21790973,21880262, 22129055, 22477146, 134 22914293, 25157823, 26109647, 26469693STK4 AR Public PMID: 19782549, 23765059, 23887241, 24753205, 26029204441 db STX11 AR Public PMID: 19302049, 21881043, 24916509, 26454313 442db STXBP2 AD AR Public PMID: 21881043, 24916509, 25564401, 26454313 443db SYNCRIP unknown PBio PMID: 10734137, 18045242, 19331829, 19232660,22493061, 444 22935615, 23679954, 23700384, 24844655, 25100733, 26641092T AD AR PBio PMID: 11897834, 17438107, 23064415, 23662285, 24253444, 44524556085, 25186612, 26210634, 26919728 TAP1 AR Public PMID: 26454313 446db TAP2 AR Public PMID: 26454313 447 db TAPBP unknown Public PMID:26454313 448 db TAZ XLR Public PMID: 20008220 449 db TBC1D16 unknownPBio PMID: 16923123, 19077034, 21250943, 23019362, 23485563, 13623812537, 24513270, 26030178 TBK1 AD Public PMID: 23887241, 25930993,26513235, 28049150 450 db TBX1 AD Public PMID: 26454313 451 db TCIRG1 ADAR Public MySql; PMID 19507210, 19782549, 24753205, 27233968 452 dbTICAM1 AD AR Public PMID: 22105173, 23887241, 25764117, 25930993,26513235, 453 db 28049150 TLR3 AD Public PMID: 23592984, 23887241,25930993, 26513235, 27810922, 454 db 27873163, 27881733 TLR4 associationBoth PMID: 12124407, 17893200, 18946062, 19843948, 20521908, 45521677132, 22474023, 22962435, 23055527, 23890253, 25365308, 25454804,25930993, 26189680, 26453379, 27881733 TMEM173 AD Public PMID: 23388631,25645939, 25692705, 26052098, 27260006, 456 db 27801882, 27821552 TNFassociation Public MySql; PMID: 27042682 457 db TNFAIP3 AD Public PMID:23969028, 26642243, 27845235 458 db TNFRSF10A unknown PBio PMID:10889508, 11602752, 11704827, 11777550, 11844843, 138 12390973,12694389, 14975593, 15007095, 16394652, 16554480, 17671142, 19690337,20921531 TNFRSF11A AD AR Public PMID: 17088646, 17360404, 18281276,18606301, 19380800, 459 db 19507210, 25102334, 25393853, 27003757,27016605 TNFRSF11B AR Public PMID: 19507210, 25102334, 25393853,27003757 460 db TNFRSF13B AD AR Public MySql; PMID: 17467261, 17492055,18978466, 18981294, 461 db 19629655, 20889194, 21458042, 22697072,23765059, 25454804, 25930993, 26727773, 27123465 TNFRSF13C AR BothMySql; PMID: 16769579, 17785824, 18784835, 18813230, 139 19136305,19406831, 20547827, 20547828, 20817206, 21897850, 22028296, 22030463,23684423, 24101550, 24953530, 25454804, 25637018, 25724205, 26419927,26453379, 26600308, 26888554 TNFRSF18 unknown PBio PMID: 16439533,19162554, 19363449, 22017440, 23432692, 140 24484736, 25738498 TNFRSF4AR Public MySql 462 db TNFRSF8 unknown PBio PMID: 10921351, 15990453,16472805, 18852356, 20141444, 463 20378007, 21933041, 23115213,23307550, 23654079, 24809535, 25999451 TNFSF11 AR Public PMID: 17088646,17360404, 18281276, 18606301, 19507210, 464 db 25992615, 27003757TNFSF12 association Public PMID: 23765059 465 db TP53 AD AR PublicMySql; PMID: 11048806, 11079782, 12009037, 19282432, 466 db 26870672TRAF3 AD Public PMID: 20832341, 23887241, 25764117, 25930993, 28049150467 db TRAF6 unknown Public PMID: 10215628, 10421844, 25200954,27808398, 27999438 468 db TRAFD1 unknown PBio PMID: 16221674, 18849341,23913580, 25909814, 25992615, 141 26283173 TREX1 AD AR Public PMID:26052098, 27260006, 27821552 469 db TRNT1 AR Public MySql; PMID:25193871 470 db TRPM2 unknown PBio PMID: 9806837, 16585058, 18569867,19411837, 20107186, 142 25012489, 25049394, 25088676, 26300888,26558786, 26679996, 26942016, 26969190, 27405665, 27872485 TTC7A ARPublic MySql; PMID: 27873163 471 db UBE2N unknown PBio PMID: 21512573,23159053, 24906799, 25343992, 25503582, 145 25548215, 26085214,26150489, 26212332, 26518362 UNC119 AD Public MySql 472 db UNC13D ARPublic PMID: 19302049, 21881043, 24916509, 25564401, 25980904, 473 db26454313 UNC93B1 association Public PMID: 23810987, 23887241, 25930993,27873163 474 db UNG AR Public MySql; PMID: 475 db 23765059 USP18 ARPublic PMID: 27016605, 27325888, 27801882, 27821552 476 db USP20 unknownPublic PMID: 27801882 477 db VAPA unknown PBio PMID: 9657962, 10523508,10655491, 11511104, 12931207, 478 18713837, 23536298, 24076421,24569996, 25015719 VCP AD Public PMID: 24248593, 27730320 479 db VDAC1unknown PBio PMID: 10620603, 25874870, 26322231, 26542804, 26616244, 48026758954, 26878172 VPS13B AR Public PMID: 20008220, 20301655 481 dbVPS45 AR Public MySql; PMID: 23738510, 24145314, 24164830, 26358756 482db VSTM1 unknown PBio PMID: 22960280, 23436183, 24205237, 25351446,25887911, 147 26760041 VWA2 unknown PBio PMID: 14506275, 18434322,21385852, 23443151, 23960233, 148 26121272 WEE1 unknown Public PMID:19903823, 25088202, 26598692, 26881506, 27042682 484 db WIPF1 AR PublicPMID: 23765059, 26029204, 26453379 485 db XIAP XLD XLR Public MySql;PMID: 22365665, 25744037, 26953272 486 db YBX1 unknown Public PMID:27042682 487 db YWHAZ unknown Both PMID: 25894827, 27042682 488 ZAP70 ADAR Public PMID: 18219311, 23494777, 23765059, 24164480, 26454313 489 dbZBTB24 AR Public MySql; PMID: 23486536, 23765059, 26851945, 27098601 490db

Table 6 is a comprehensive list of 419 exemplary genes (referred toherein as ‘PML-419 genes’ or ‘PML-419 gene list’) interrogated in thepresent study, along with information related to the inheritance patternassumed for analysis and the reason for inclusion of the gene. Genesources for Table 6 (column heading ‘Gene Source’): 1) nominated on thebasis of being linked to immune deficiency, as curated from publicdatabases (indicated by ‘Public db’) such as PubMed and ClinVar, 2) PBioCNV-identified genes (‘PBio’, see Table 6 column heading ‘Gene Source’)from a genome-wide array CGH gene discovery study of 71 PML cases, or 3)curated from public databases and identified in PBio's PML genediscovery study (indicated by ‘Both’). A genetic predisposition to PMLon the basis of the host's genome was proposed; that is, germlinegenetic variant(s) in the PML patient's genome, rather than geneticvariants that are present in the JC virus, are the cause of thepatient's PML (Hatchwell, Front Immunol., 6:216 (2015). Details on thesource of the genes in the PML-419 gene list can be found in thefollowing immunodeficiency and immune-related gene sources: Durandy etal., Nat Rev Immunol., 13(7):519-33 (2013); Milner et al., Nat RevImmunol., 13(9):635-48 (2013); Paciolla et al., Genes Immun.,16(4):239-46 (2015); Hatchwell, Front Immunol., 6:216 (2015); Thijssenet al., Nat Commun., 6:7870 (2015); Chinn et al., Immunol Allergy ClinNorth Am., 35(4):671-94 (2015); Zhou et al., Nat Genet., 48(1):67-73(2015); Navabi et al., Allergy Asthma Clin Immunol., 12:27 (2016); andTsujita et al., J Allergy Clin Immunol. (2016). MySql′ genes are derivedfrom the ClinVar database. ClinVar was searched using the terms “immunedeficiency” and “immunodeficiency.” Entries that described large genomicrearrangements, containing multiple genes, were excluded. Anon-redundant list of 125 genes was compiled by combining the output ofthe two searches and deposited into a MySQL database. NOTE: A subset ofthese genes are not flagged as ‘MySql’ if they appeared in one or moreof the immune gene review papers noted above. van der Kolk et al., AnnClin Transl Neurol.; 3(3):226-32 (2016) was the source of known BAG3 PMLgene (see below) and 28 candidate PML genes on the basis of connectionto JCV. Van der Kolk et al., cite a method as follows: “the latter wasperformed by searching for JCV in NCBI, and selecting for genes inhumans.” This yielded 30 human genes, 5 of which overlapped with the PMLgene list and 2 genes (HLA-DQB1, HLA-DRB1) were excluded because HLAloci are difficult to interpret. The genes ADA, BAG3, BTK, CD40LG,DOCK8, STAT1, WAS, and WIPF1 were derived from Hatchwell, FrontImmunol., 6:216 (2015) (see Table 1 for primary references); van derKolk et al., Ann Clin Transl Neurol., 3(3):226-32 (2016); and Zerbe etal., Clin Infect Dis., 62(8):986-94 (2016). PBio genes are based on CNVstudies and a subset overlap the immune review gene lists (annotated as‘Both’ in column heading ‘Gene Source’). Tier 1 genes were used aspotential solutions for PML cases. Determination of Autosomal Dominant(AD), Autosomal Recessive (AR), X-linked dominant (XLD), or X-linked(XLR) disease model for each gene was derived from the immunodeficiencyreview papers and/or OMIM annotations. Entries marked ‘association’denotes variants were found to be associated with an immune-relatedcondition; ‘unknown’ denotes no evidence reported in the literature foran AD or AR model.

TABLE 7 Potential cause of PML in each patient in the study VarianFrequency Frequency RefSeq Details (Reciprocol) Primary Gene Variant(Ethnic (Ethnic SEQ Sample ID Ethnicity Gender Disease Symbol Typespecific) specific) ID MVGS1116-8a EUR F MS (NZ Rx) DOCK8 SNV hom 0.4991 in 1,792 1147 SNV het 0.00447 1148 MVGS1359 EUR F MS (NZ Rx) IL17F SNVhet 0.00024 1 in 4,170 1114 MVGS1368 EUR F MS (NZ Rx) IDO2 SNV hom 0.5081 in 121 1125 SNV het 0.065 1126 MVGS540-3746 EUR M MS (NZ Rx SHARPINSNV hom 0.00217 1 in 461 1142 MVGS540-3936 EUR F MS (NZ Rx) DOCK8 SNVhom 0.499 1 in 5,246 1147 SNV het 0.00153 1154 SNV het 0.194 1152MVGS694-6a EUR F Other CHD7 SNV het 0.00028 1 in 3,528 1135 MVGS811-13aEUR M HIV PIK3CD PIK3CD-AS1 CNV hom novel 0 2 MVGS995-4a EUR M MS (NZRx) EPG5 SNV hom 0.495 1 in 32,224 1279 SNV het 0.000251 1273 PML01 EURF HIV ITSN2 SNV hom 0.00183 1 in 547 1028 PML02 EUR M Other IKBKB SNVhet novel 0 1127 PML03 EUR F MS (NZ Rx) FPR2 CNV hom 2.23E−06 1 in448,833 140 PML04 EUR M HIV unsolved n/a n/a n/a n/a PML05 LAT M HIVTBK1 SNV het novel 0 1203 PML06 AFR M HIV TICAM1 SNV het 0.000777 1 in1,287 1289 PML09 EUR M HIV LIG4 SNV 0.00399 1 in 3497 1221 SNV comp het0.287 1222 PML10 EUR F HIV TNFRSF11A SNV het novel 0 1287 PML12 LAT FHIV BLM SNV hom 0.000874 1 in 1,144 1235 PML13 AFR M HIV PLCG2 SNV0.00167 1 in 128,105 1261 SNV comp het 0.0187 1263 PML14 EUR M HIV PLCG2SNV 0.00998 1 in 25,259 1261 SNV comp het 0.0159 1263 PML15 LAT M HIVNOD2 SNV het novel 0 1255 PML16 AFR F HIV TNFRSF11A SNV het novel 0 1287PML17 EUR M HIV ZAP70 SNV het 0.00009 1 in 11,110 1035 PML18 EUR M HIVunsolved n/a n/a n/a n/a PML19 AFR M HIV ATM SNV 0.0479 0 1193 SNV comphet novel 1194 PML20 AFR M HIV NFKB1 SNV het 0.00173 1 in 577 1069 PML21EUR M HIV ZAP70 SNV het 0.0000602 1 in 16,623 1034 PML22 EUR M HIVunsolved n/a n/a n/a n/a PML23 EUR F HIV DCLRE1C SNV hom novel 0 1167PML25 EUR F HIV PLCG2 SNV het 0.000150 1 in 6,672 1259 PML26 EUR M HIVTRAFD1 SNV hom 0.000689 1 in 1,451 1208 PML27 EUR M HIV TAP2 SNV hom0.00837 1 in 120 1101 PML28 EUR F MS (NZ Rx) TRPM2 SNV hom novel 0 1311PML29 AFR M HIV KCTD7 RABGEF 1 CNV hom 0.000387 1 in 2,584 65 PML30 EURM HIV TNFRSF11A SNV het novel 0 1287 PML31 AFR F HIV DDX58 SNV het0.000779 1 in 1,283 1157 PML32 EUR M HIV unsolved n/a n/a n/a n/a PML33EUR M HIV TNFRSF11A SNV het novel 0 1287 PML35 EUR F HIV TNFRSF11A SNVhet novel 0 1287 PML36 AFR F HIV TCIRG1 SNV het 0.002134 1 in 469 1184PML37 AFR M HIV GATA2 SNV het novel 0 1056 PML38 EUR M HIV MALL CNV hom3.95E−06 1 in 253,036 26 PML39 AFR M HIV unsolved n/a n/a n/a n/a PML40LAT F HIV PNPT1 SNV hom novel 0 1032 PML41 AFR M HIV ZAP70 SNV het novel0 1036 PML43 EUR M HIV PTPRC SNV hom novel 0 1020 PML44 EUR M HIVTNFRSF11A SNV het novel 0 1287 PML45 EUR F Other CARD11 SNV het 0.0024 1in 417 1123 PML46 LAT M HIV EPG5 SNV 0.0123 1 in 745 1278 SNV comp het0.436 1279 PML48 EUR M HIV SMAD4 SNV het 0.000901 1 in 11,100 1284 PML49EUR M HIV STIM1 SNV het novel 0 1174 PML50 AFR M HIV NOD2 SNV het novel0 1256 PML51 EUR M HIV TICAM1 SNV het 0.00265 1 in 377 1289 PML52 EUR FOther unsolved n/a n/a n/a n/a PML53 EUR M Other GFI1 SNV het 0.00003 1in 32,635 1011 PML54 EUR F HIV TNFRSF11A SNV het novel 0 1287 PML55 EURF HIV RTEL1 SNV het 0.00326 1 in 307 1299 PML56 EUR M HIV TNFRSF11A SNVhet novel 0 1287 PML57 EUR F Other TRAF3 SNV het 0.00093 1 in 1,075 1229PML58 AFR M HIV DOCK8 SNV 0.0575 1 in 146 1146 SNV comp het 0.478 1147PML59 AFR M HIV IFIH1 SNV het 0.00281 1 in 356 1040 PML60 EUR M HIVunsolved n/a n/a n/a n/a PML61 AFR F HIV TNFRSF11A SNV het novel 0 1287PML62 AFR F HIV unsolved n/a n/a n/a n/a PML63 AFR M HIV PLCG2 SNV het0.00195 1 in 514 1260 PML64 AFR M HIV PIK3R1 SNV het novel 0 1077 PML65AFR M HIV ITSN2 CNV hom 0.00313 1 in 319 14 PML66 AFR M HIV unsolved n/an/a n/a n/a PML67 EUR F MS (NZ Rx) unsolved n/a n/a n/a n/a (CNV data,no WES data) PML68 EUR F MS (NZ Rx) LRBA SNV hom 0.00162 1 in 618 1073PML69 EUR M Other EGR1 ETF1 CNV hom 0.001 1 in 1,005 45 PML72 AFR F HIVNOD2 SNV het 0.004036 1 in 248 1252

Table 7 contains a single genetic solution/explanation that is thepotential cause of PML in each patient in the study (71 cases wereassessed with genome-wide array CGH and 71 were also assessed by wholeexome sequencing), with the exception of 19 ‘unsolved’ cases. Solutionsare based on a combination of CNV and SNV variants, connected by SEQ IDsto tables 1, 4 and 5. For homozygous or compound heterozygous variantsolutions, expected population frequencies were calculated as follows:

Expected population frequency for variant a (freq p) and variant b (freqq)=pq/4.

For example, PMLO9 has 2 variants, SEQID 1221 and 1222, with individualfrequencies in the normal population of 0.00399, 0.287. The expectedfrequency in an ethnically-matched normal population for thiscombination is (0.00399*0.287)*0.25=0.000286283=1/3,497.

The Primary Disease identifiers in Table 7 are: HIV, infection withhuman immunodeficiency virus; MS (NZ Rx), multiple sclerosis treatedwith natalizumab; Other, which includes a variety ofdisorders/conditions (MVGS694-6a had aplastic anemia, PML02 and PML52had lymphoma, PML45 and PML 57 had chronic lymphocytic leukemia, PML53had sarcoidosis, and PML69 is a kidney transplant patient who was onbelatacept).

Solutions were considered on the basis of presence of rare variants(CNVs and/or SNVs) in or near genes that are listed in Table 6. Bothautosomal recessive (AR) and autosomal dominant (AD) disease modelscomprise this set of solutions, based on finding homozygous SNVs,homozygous CNVs, compound heterozygous SNVs, or heterozygous SNVs. NinePML cases in Table 7 were considered ‘unsolved’ on the basis ofanalyzing both CNV and SNV data, and one case (PML67) was assessed forCNVs only since WES data were unavailable. In some instances, a case wasconsidered unsolved for a best solution (Table 7) but alternatesolutions were reported in Table 8 (see below).

For PML cases that had more than one potential solution. In theseinstances, the ‘best’ solution (Table 7) was determined on the basis ofrarity of the genetic variant(s) and the relative strength of thebiology for the PML-419 genes (Table 6). Alternate solutions arereported in Table 8. For example, for PML case MVGS1116-8a, threesolutions were found, which impacted genes DOCK8, HIVEP2, and RNF168. Inthis example, DOCK8 compound heterozygous SNVs (Table 7, SNV hom and SNVhet) were selected as the best solution because DOCK8 is a known PMLgene. In another example, PML case MVGS1359 has IL17F (het SNV) listedas the best solution in Table 7 because it is rarer than alternatesolutions for the ATR and STXBP2 genes.

While some PML patients may have multiple genes/variants causing and/orcontributing to their PML, in many PML patients only a single gene willbe the primary cause analogous to patients diagnosed with primaryimmunodeficiency disorders. In addition to the alternate solutionsreported in Table 8, which are based on SNV genetic findings only,additional alternate solutions based on CNV genetic findings arereported in Table 1.

TABLE 8 Alternate genetic solutions/explanations as the potential causeof PML in the study Variant Frequency RefSeq Frequency (Reciprocol) GeneDetails (Ethnic (Ethnic Sample ID Symbol Variant Type specific)specific) SEQ ID MVGS1116-8a HIVEP2 SNV het novel 0 1118 MVGS1116-8aRNF168 SNV hom 0.469 1 in 1,041 1063 SNV het 0.00818 1066 MVGS1359 ATRSNV het 0.00393 1 in 254 1058 MVGS1359 STXBP2 SNV het 0.00501 1 in 1991291 MVGS540-374b MKL1 CNV hom 3.99E−08 1 in 25,081,515 157 MVGS540-393bPRKDC SNV het 0.00097 1 in 1,031 1130 MVGS811-13a CLCN7 SNV het 0.000281 in 3,571 1239 MVGS995-4a KAT6B SNV het 0.00003 1 in 33,357 1169MVGS995-4a PRF1 SNV het 0.00243 1 in 412 1168 PML03 CDKN1B SNV het0.00003 1 in 32,209 1200 PML05 ATR SNV het novel 0 1061 PML05 NFKB1 SNVhet 0.00501 1 in 200 1070 PML06 CHD7 SNV het 0.00797 1 in 125 1136 PML06DOCK8 SNV hom 0.478 1 in 267 1147 SNV het 0.0313 1152 PML09 RIPK3 SNVhet 0.00398 1 in 251 1227 PML10 JUN SNV het 0.00103 1 in 968 1009 PML10RAG1 SNV het 0.00039 1 in 2,566 1179 PML12 CARD11 SNV het novel 0 1122PML12 PRKDC SNV het novel 0 1128 PML13 DOCK8 SNV hom 0.478 1 in 267 1147SNV het 0.0313 1152 PML13 IRAK4 SNV het novel 0 1202 PML13 PIK3CD SNVhet 0.00679 1 in 147 1000 PML14 NBN SNV het 0.0039 1 in 256 1138 PML14NFKB1 SNV het novel 0 1071 PML15 ASH1L SNV Novel 0 1016 SNV comp het0.0019 1017 PML15 CHD7 SNV het 0.00176 1 in 568 1133 PML15 HIVEP2 SNVhet novel 0 1116 PML15 STIM1 SNV het 0.00587 1 in 170 1175 PML16 TBK1SNV het novel 0 1204 PML16 TLR3 SNV het 0.00136 1 in 738 1076 PML17APOL1 SNV het 0.0021 1 in 475 1327 PML18 PKHD1 SNV hom 0.498 1 in 1711104 SNV het 0.0471 1107 PML19 DOCK8 SNV 0.0575 1 in 146 1146 SNV comphet 0.478 1147 PML19 IFIH1 SNV het 0.00444 1 in 225 1041 PML20 JUN SNVhet 0.00535 1 in 187 1010 PML21 PRKCH SNV het novel 0 1228 PML21 PSTPIP1SNV het 0.00093 1 in 1,074 1232 PML21 RAG2 SNV het novel 0 1182 PML22RIPK3 SNV hom 0.00309 1 in 324 1226 PML22 VPS45 SNV het 0.00114 1 in 8781014 PML23 NOD2 SNV het novel 0 1251 PML23 RAG1 SNV het 0.00003 1 in33,317 1180 PML28 PKHD1 SNV hom 0.498 1 in 171 1104 SNV het 0.0471 1107PML28 TNFRSF13B SNV het 0.00929 1 in 108 1267 PML30 RTEL1 SNV het0.000124 1 in 8,068 1300 PML31 AP3B1 SNV het novel 0 1084 PML31 PRKDCSNV het novel 0 1129 PML33 STIM2 SNV het 0.00003 1 in 32,688 1068 PML33TLR3 SNV hom 0.413 1 in 2,227 1075 SNV het 0.00435 1074 PML33 TLR4 SNVhom 0.00283 1 in 354 1161 SNV hom 0.00285 1160 PML35 PRKCB SNV het0.00276 1 in 362 1247 PML36 NOD2 SNV het 0.00871 1 in 115 1254 PML36PIK3CD SNV het 0.00679 1 in 147 1000 PML37 AP3B1 SNV het novel 0 1080PML37 ATR SNV het 0.00038 1 in 2,601 1059 PML37 WEE1 SNV het 0.00825 1in 121 1177 PML38 MYD88 SNV het novel 0 1051 PML40 MCEE SNV hom 0.01 1in 100 1033 PML41 AP3B1 SNV het 0.00173 1 in 577 1082 PML41 CHD7 SNV hetnovel 0 1137 PML41 DOCK8 SNV 0.0575 1 in 146 1146 SNV comp het 0.4781147 PML41 POLE SNV hom 0.00019 1 in 5,203 1219 PML41 RNF168 SNV 0.412 01063 SNV comp het novel 1062 PML43 DOCK8 SNV hom 0.499 0 1147 SNV hetnovel 1150 PML44 DCLRE1C SNV hom 0.0287 1 in 174 1166 SNV hom 0.005751165 PML44 GFI1 SNV het 0.00708 1 in 141 1012 PML45 POLA1 SNV het novel0 1328 PML46 AP3B1 SNV het 0.00587 1 in 170 1082 PML46 IL21R SNV het0.00573 1 in 175 1248 PML46 PRKDC SNV het 0.00017 1 in 5,781 1131 PML48TNFRSF11A SNV het 0.00233 1 in 429 1286 PML49 DCLRE1C SNV hom 0.00575 1in 174 1166 SNV hom 0.0287 1165 PML49 PTEN SNV het novel 0 1171 PML49RIPK1 SNV het 0.00090 1 in 1,112 1090 PML50 AP3B1 SNV het 0.00387 1 in259 1078 PML50 PIAS2 SNV het 0.00357 1 in 280 1283 PML50 STXBP2 SNV het0.00038 1 in 2,598 1290 PML52 GFI1 SNV het 0.00708 1 in 141 1012 PML53IL1B SNV het novel 0 1037 PML53 STXBP2 SNV het 0.00501 1 in 199 1291PML54 EPG5 SNV 0.0638 1 in 127 1278 SNV comp het 0.495 1279 PML54 IFNGR2SNV het 0.00009 1 in 11,096 1304 PML54 RAG1 SNV het 0.00003 1 in 33,3521178 PML54 RAG2 SNV het novel 0 1183 PML57 PIAS1 SNV het novel 0 1231PML57 PKHD1 SNV hom 0.498 1 in 171 1104 SNV het 0.0471 1107 PML57 SKIV2LSNV hom 0.157 1 in 538 1098 SNV hom 0.214 1100 SNV het 0.0471 1099 PML58GFI1 SNV het 0.00144 1 in 693 1012 PML59 IFNLR1 SNV het novel 0 1002PML59 NOD2 SNV het 0.00404 1 in 248 1252 PML59 NRIP1 SNV hom 0.00711 1in 141 1301 PML59 RAD51 SNV het 0.00865 1 in 116 1230 PML60 MAPK3 SNVhet novel 0 1250 PML60 TP53 SNV het 0.00048 1 in 2,085 1266 PML61 GATA2SNV het 0.00024 1 in 4,139 1057 PML61 PTPRC SNV hom novel 0 1019 PML61TNFRSF8 SNV het novel 0 1001 PML62 PRKCD SNV het novel 0 1054 PML63HTR2A SNV hom 0.00519 1 in 193 1220 PML63 MAPK3 SNV het 0.00193 1 in 5181249 PML64 PLCG2 SNV het 0.00044 1 in 2,276 1264 PML64 WEE1 SNV hetnovel 0 1176 PML65 IRAK4 SNV het 0.00118 1 in 850 1201 PML66 PIK3CD SNVhet 0.00679 1 in 147 1000 PML68 RAG1 SNV het 0.00586 1 in 171 1181 PML72CARD11 SNV het 0.00242 1 in 413 1121 PML72 HIVEP1 SNV hom 0.00164 1 in610 1092 PML72 IFIH1 SNV het 0.00843 1 in 119 1043

Table 8 contains analogous information to Table 7, with the exceptionthat Ethnicity, Gender and Primary Disease are not repeated. Table 8contains alternate genetic solutions/explanations as the potential causeof PML for the patients in the study (71 cases were assessed withgenome-wide array CGH and 70 were also assessed by whole exomesequencing). Solutions in Table 8 are also case-level and representsecondary, alternative solutions for the cases listed (using the samecriteria used to identify potential solutions reported in Table 7). Inother words, for some individuals, more than one reasonable solution wasidentified and, while those in Table 7 are considered the most likely,those in Table 8 are also potential solutions. It can be appreciated bythose skilled in the art that further data on new PML cases, patientswith genetic-based immunodeficiency disorders, or functional studies ona given gene may support selection of a Table 8 solution as the ‘best’single solution (e.g., a current Table 7 solution could be consideredinstead as a Table 8 solution, and vice versa).

TABLE 9 Pairs of SNVs impacting the same gene Variant Frequency RefSeqAmino Details SEQ Gene Variant Ref Alt Acid (Ethnic ID Sample ID SymbolType Chromosome Position Allele Allele Change specific) NO MVGS1359TTC7A SNV het 2 47273468 A G K252R 0.00684 1030 MVGS1359 TTC7A SNV het 247277182 T C S318P 0.00683 1031 MVGS1368 RNF168 SNV het 3 196199204 G TP401Q 0.46947 1063 MVGS1368 RNF168 SNV het 3 196210764 T C n/a 0.000031065 MVGS1368 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 MVGS1368TLR4 SNV het 9 120475602 C T T359I 0.10560 1161 MVGS811-13a HIVEP1 SNVhet 6 12121113 C T P362L 0.00024 1091 MVGS811-13a HIVEP1 SNV het 612123538 G T K1170N 0.08730 1093 MVGS995-4a EEA1 SNV het 12 93196332 C TE840K 0.01949 1206 MVGS995-4a EEA1 SNV het 12 93205148 T G E702D 0.000031207 PML02 RBFOX1 SNV het 16 7759119 G A G326S 0.00504 1245 PML02 RBFOX1SNV het 16 7759496 C T P401S novel 1246 PML04 POLE SNV het 12 133220526T C N1369S 0.22363 1213 PML04 POLE SNV het 12 133237658 T G Q766P novel1215 PML05 TLR4 SNV het 9 120475302 A G D259G 0.04628 1160 PML05 TLR4SNV het 9 120475602 C T T359I 0.04180 1161 PML05 POLE SNV het 12133220526 T C N1369S 0.12669 1213 PML05 POLE SNV het 12 133252406 C AA121S novel 1217 PML10 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160PML10 TLR4 SNV het 9 120475602 C T T359I 0.10560 1161 PML12 IDO2 SNV het8 39840234 A G I127V 0.38971 1124 PML12 IDO2 SNV het 8 39862881 C TR235W 0.50282 1125 PML12 IDO2 SNV het 8 39862893 T A S239T 0.02384 1126PML13 STX11 SNV het 6 144508353 G A V197M novel 1119 PML13 STX11 SNV het6 144508563 G A V267M 0.00202 1120 PML13 DCLREIC SNV het 10 14974905 T CH123R 0.16298 1165 PML13 DCLREIC SNV het 10 14976727 G C P171R 0.222951166 PML13 EPG5 SNV het 18 43497710 A G V1058A 0.42740 1279 PML13 EPG5SNV het 18 43531186 C T S424N 0.00600 1282 PML14 ATM SNV het 11108117787 C T S333F 0.00280 1188 PML14 ATM SNV het 11 108175462 G AD1853N 0.24654 1193 PML14 TRPM2 SNV het 21 45815425 C G I621M novel 1313PML14 TRPM2 SNV het 21 45845699 G A V1242M 0.00537 1321 PML16 TLR3 SNVhet 4 187004074 C T L135F 0.12378 1075 PML16 TLR3 SNV het 4 187005854 AC I571L 0.00136 1076 PML16 HIVEP1 SNV het 6 12121113 C T P362L 0.078561091 PML16 HIVEP1 SNV het 6 12162068 C T S160F 0.01979 1096 PML16 PKHD1SNV het 6 51483961 T C Q4048R 0.50029 1104 PML16 PKHD1 SNV het 651747943 T A D2433V 0.07153 1112 PML16 POLE SNV het 12 133209020 G CQ2044E novel 1212 PML16 POLE SNV het 12 133220526 T C N1369S 0.248891213 PML17 RNF168 SNV het 3 196199204 G T P401Q 0.46947 1063 PML17RNF168 SNV het 3 196210704 G A P206L 0.00003 1064 PML17 HIVEP1 SNV het 612123538 G T K1170N 0.08730 1093 PML17 HIVEP1 SNV het 6 12125232 C TS1735F 0.00027 1095 PML17 PKHD1 SNV het 6 51483961 T C Q4048R 0.498371104 PML17 PKHD1 SNV het 6 51497503 C A R3842L 0.04707 1107 PML17DCLRE1C SNV het 10 14974905 T C H123R 0.27332 1165 PML17 DCLRE1C SNV het10 14976727 G C P171R 0.13896 1166 PML17 ATM SNV het 11 108119823 T CV410A 0.00643 1189 PML17 ATM SNV het 11 108175462 G A D1853N 0.246541193 PML17 EPG5 SNV het 18 43464763 C T G1708D 0.00013 1274 PML17 EPG5SNV het 18 43497710 A G V1058A 0.49513 1279 PML18 TLR4 SNV het 9120475302 A G D259G 0.10251 1160 PML18 TLR4 SNV het 9 120475602 C TT359I 0.10560 1161 PML20 AK2 SNV het 1 33476435 C A n/a novel 1003 PML20AK2 SNV het 1 33478900 T A Y159F 0.04954 1004 PML20 HIVEP1 SNV het 612124215 C T P1396L 0.06774 1094 PML20 HIVEP1 SNV het 6 12163657 C TP2374S 0.06733 1097 PML20 KANK1 SNV het 9 711359 C T S198F 0.11985 1155PML20 KANK1 SNV het 9 713132 G T G631V 0.00136 1156 PML21 DOCK8 SNV het9 286593 C A P29T 0.49889 1147 PML21 DOCK8 SNV het 9 286593 C A P29T0.49889 1147 PML21 DOCK8 SNV het 9 312134 G A E169K 0.06358 1149 PML21DOCK8 SNV het 9 312134 G A E169K 0.06358 1149 PML21 TLR4 SNV het 9120475302 A G D259G 0.10251 1160 PML21 TLR4 SNV het 9 120475302 A GD259G 0.10251 1160 PML21 TLR4 SNV het 9 120475602 C T T359I 0.10560 1161PML21 TLR4 SNV het 9 120475602 C T T359I 0.10560 1161 PML21 ATM SNV het11 108138003 T C F858L 0.02864 1191 PML21 ATM SNV het 11 108138003 T CF858L 0.02864 1191 PML21 ATM SNV het 11 108143456 C G P1054R 0.050691192 PML21 ATM SNV het 11 108143456 C G P1054R 0.05069 1192 PML21 TRPM2SNV het 21 45786650 C T S146F 0.00072 1305 PML21 TRPM2 SNV het 2145786650 C T S146F 0.00072 1305 PML21 TRPM2 SNV het 21 45820196 C TR735C 0.10374 1314 PML21 TRPM2 SNV het 21 45820196 C T R735C 0.103741314 PML22 SKIV2L SNV het 6 31928306 A G Q151R 0.15759 1098 PML22 SKIV2LSNV het 6 31935750 G A V724M 0.04718 1099 PML22 SKIV2L SNV het 631936679 C T A1071V 0.21419 1100 PML22 DOCK8 SNV het 9 286593 C A P29T0.49889 1147 PML22 DOCK8 SNV het 9 304628 G A R151Q 0.00447 1148 PML22GDPD4 SNV het 11 76954833 G A H383Y 0.44867 1186 PML22 GDPD4 SNV het 1176979511 A G 1233T 0.00504 1187 PML22 ATM SNV het 11 108117787 C T S333F0.00280 1188 PML22 ATM SNV het 11 108175462 G A D1853N 0.24654 1193PML22 BLM SNV het 15 91306241 G A R643H 0.00799 1233 PML22 BLM SNV het15 91341543 A C N1112H novel 1238 PML23 PKHD1 SNV het 6 51483961 T CQ4048R 0.49837 1104 PML23 PKHD1 SNV het 6 51497503 C A R3842L 0.047071107 PML23 SHARPIN SNV het 8 145154222 G A P294S 0.08789 1142 PML23SHARPIN SNV het 8 145154257 C G S282T 0.14880 1144 PML23 DOCK8 SNV het 9286491 G A D63N 0.27362 1146 PML23 DOCK8 SNV het 9 334277 G A R325H0.00015 1151 PML25 SKIV2L SNV het 6 31928306 A G Q151R 0.15759 1098PML25 SKIV2L SNV het 6 31935750 G A V724M 0.04718 1099 PML25 SKIV2L SNVhet 6 31936679 C T A1071V 0.21419 1100 PML25 PKHD1 SNV het 6 51483961 TC Q4048R 0.49837 1104 PML25 PKHD1 SNV het 6 51524409 G T S3505R 0.020491109 PML25 EPG5 SNV het 18 43445601 T G 1174L novel 1270 PML25 EPG5 SNVhet 18 43531186 C T S424N 0.02391 1282 PML27 LYST SNV het 1 235897907 CT G2804D 0.00114 1024 PML27 LYST SNV het 1 235909815 A T F165Y 0.001021025 PML27 EPG5 SNV het 18 43445601 T G I174L novel 1270 PML27 EPG5 SNVhet 18 43497710 A G V1058A 0.49513 1279 PML29 LIG1 SNV het 19 48631258 GA T546I 0.07515 1292 PML29 LIG1 SNV het 19 48639022 T C M412V 0.053851293 PML30 DCLRE1C SNV het 10 14974905 T C H123R 0.27332 1165 PML30DCLRE1C SNV het 10 14976727 G C P171R 0.13896 1166 PML30 ATM SNV het 11108138003 T C F858L 0.02864 1191 PML30 ATM SNV het 11 108143456 C GP1054R 0.05069 1192 PML30 ATM SNV het 11 108186610 G A G2023R 0.004651195 PML31 LYST SNV het 1 235897907 C T G2804D 0.23000 1024 PML31 LYSTSNV het 1 235909815 A T F165Y 0.15155 1025 PML31 PKHD1 SNV het 651483961 T C Q4048R 0.50029 1104 PML31 PKHD1 SNV het 6 51524339 C GE3529Q 0.07244 1108 PML31 PKHD1 SNV het 6 51747943 T A D2433V 0.071531112 PML31 PKHD1 SNV het 6 51798908 C T G2041S 0.00173 1113 PML32 PKHDISNV het 6 51483961 T C Q4048R 0.49837 1104 PML32 PKHD1 SNV het 651491885 G A Q3899* novel 1106 PML32 EPG5 SNV het 18 43496539 G A S1083L0.06375 1278 PML32 EPG5 SNV het 18 43497710 A G V1058A 0.49513 1279PML32 EPG5 SNV het 18 43529551 C T V466M 0.00006 1281 PML33 AK2 SNV het1 33476435 C A n/a novel 1003 PML33 AK2 SNV het 1 33487007 C T S129N0.01100 1005 PML33 EPG5 SNV het 18 43497710 A G V1058A 0.49513 1279PML33 EPG5 SNV het 18 43523240 C T M610I 0.00066 1280 PML35 RNF168 SNVhet 3 196199204 G T P401Q 0.46947 1063 PML35 RNF168 SNV het 3 196214320C T E170K 0.00818 1066 PML36 IDO2 SNV het 8 39862881 C T R235W 0.461081125 PML36 IDO2 SNV het 8 39862893 T A S239T 0.01135 1126 PML39 LYST SNVhet 1 235897907 C T G2804D 0.23000 1024 PML39 LYST SNV het 1 235909815 AT F165Y 0.15155 1025 PML39 NHEJ1 SNV het 2 219942026 T A Q181L 0.063241047 PML39 NHEJ1 SNV het 2 220023045 C T A14T 0.23543 1048 PML40 ATM SNVhet 11 108186631 A G I2030V 0.00173 1196 PML40 ATM SNV het 11 108186631A G I2030V 0.03446 1196 PML40 ATM SNV het 11 108198384 C G L2330V0.00035 1197 PML40 ATM SNV het 11 108198384 C G L2330V 0.00491 1197PML41 PKHD1 SNV het 6 51483961 T C Q4048R 0.50029 1104 PML41 PKHD1 SNVhet 6 51497503 C A R3842L 0.00654 1107 PML41 IDO2 SNV het 8 39840234 A GI127V 0.06350 1124 PML41 IDO2 SNV het 8 39862881 C T R235W 0.46108 1125PML45 VPS13B SNV het 8 100791158 G A E2560K 0.00964 1140 PML45 VPS13BSNV het 8 100865941 G A A3442T novel 1141 PML48 EPG5 SNV het 18 43497710A G V1058A 0.49513 1279 PML48 EPG5 SNV het 18 43531186 C T S424N 0.023911282 PML51 TRPM2 SNV het 21 45826486 G A V914I novel 1315 PML51 TRPM2SNV het 21 45855099 C T R1300W 0.00021 1322 PML53 EPG5 SNV het 1843445580 C T D181N novel 1269 PML53 EPG5 SNV het 18 43497710 A G V1058A0.49513 1279 PML56 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 PML56TLR4 SNV het 9 120475602 C T T359I 0.10560 1161 PML56 DCLRE1C SNV het 1014974905 T C H123R 0.27332 1165 PML56 DCLRE1C SNV het 10 14976727 G CP171R 0.13896 1166 PML57 CSF3R SNV het 1 36932047 C T E359K 0.01706 1006PML57 CSF3R SNV het 1 36933715 A G Y113H 0.00087 1007 PML57 TLR4 SNV het9 120475302 A G D259G 0.10251 1160 PML57 TLR4 SNV het 9 120475602 C TT359I 0.10560 1161 PML57 ATM SNV het 11 108138003 T C F858L 0.02864 1191PML57 ATM SNV het 11 108143456 C G P1054R 0.05069 1192 PML57 ATM SNV het11 108175462 G A D1853N 0.24654 1193 PML58 DOCK8 SNV het 9 399233 A GN1002D 0.19737 1153 PML58 DCLRE1C SNV het 10 14974905 T C H123R 0.162981165 PML58 DCLRE1C SNV het 10 14976727 G C P171R 0.22295 1166 PML58DNMT3B SNV het 20 31383307 G A G311S 0.00192 1296 PML58 DNMT3B SNV het20 31384614 G T G343V novel 1297 PML59 LYST SNV het 1 235897907 C TG2804D 0.23000 1024 PML59 LYST SNV het 1 235897907 C T G2804D 0.230001024 PML59 LYST SNV het 1 235909815 A T F165Y 0.15155 1025 PML59 LYSTSNV het 1 235909815 A T F165Y 0.15155 1025 PML59 LIG1 SNV het 1948631258 G A T5461 0.07515 1292 PML59 LIG1 SNV het 19 48631258 G A T546I0.07515 1292 PML59 LIG1 SNV het 19 48639022 T C M412V 0.05385 1293 PML59LIG1 SNV het 19 48639022 T C M412V 0.05385 1293 PML60 DCLRE1C SNV het 1014974905 T C H123R 0.27332 1165 PML60 DCLRE1C SNV het 10 14976727 G CP171R 0.13896 1166 PML60 POLE SNV het 12 133202816 C T E2113K 0.046861211 PML60 POLE SNV het 12 133220526 T C N1369S 0.22363 1213 PML62 TLR4SNV het 9 120475302 A G D259G 0.13066 1160 PML62 TLR4 SNV het 9120475602 C T T359I 0.02672 1161 PML63 HIVEP1 SNV het 6 12124215 C TP1396L 0.06774 1094 PML63 HIVEP1 SNV het 6 12163657 C T P2374S 0.067331097 PML63 PLCG2 SNV het 16 81942175 A G N571S 0.01870 1263 PML63 TRPM2SNV het 21 45795833 G T V297L 0.00097 1306 PML63 TRPM2 SNV het 2145815307 T C V582A 0.00724 1310 PML64 DNER SNV het 2 230231632 C T D687N0.00058 1049 PML64 DNER SNV het 2 230450646 T A T259S 0.00692 1050 PML64IDO2 SNV het 8 39862881 C T R235W 0.46108 1125 PML64 IDO2 SNV het 839862893 T A S239T 0.01135 1126 PML65 POLE SNV het 12 133201381 T AI2228F 0.00232 1210 PML65 POLE SNV het 12 133253971 C T R233Q 0.020371218 PML66 PKHD1 SNV het 6 51483961 T C Q4048R 0.50029 1104 PML66 PKHDISNV het 6 51612746 G A S3223L 0.00000 1110 PML66 PKHD1 SNV het 651712759 T C T2641A 0.04812 1111 PML66 EPG5 SNV het 18 43456296 C TR1985Q 0.07733 1271 PML66 EPG5 SNV het 18 43497710 A G V1058A 0.427401279 PML68 DCLREIC SNV het 10 14974905 T C H123R 0.27332 1165 PML68DCLREIC SNV het 10 14976727 G C P171R 0.13896 1166 PML72 PSMB8 SNV het 632810794 T A T70S 0.04224 1102 PML72 PSMB8 SNV het 6 32811752 C T G8R0.04845 1103 PML72 POLE SNV het 12 133220526 T C N1369S 0.24889 1213PML72 POLE SNV het 12 133245026 G A P477S 0.02332 1216 PML72 RBFOX1 SNVhet 16 7568296 C T P102S 0.00692 1242 PML72 RBFOX1 SNV het 16 7703891 AG T235A novel 1243

Table 9 lists, for each case (in multiple rows), variants for which itwas not possible, using the whole exome sequencing (WES) data available,to determine phase (e.g., whether two variants are in cis—on the samechromosome—or trans—on opposite chromosomes). Determining phase is animportant consideration when dealing with disorders that are beingevaluated on an autosomal recessive (AR) basis. If two variants areknown to be present but it is impossible to determine whether they arein cis or trans, then it is impossible to conclude that both gene copiesare affected, as opposed to only one (albeit with 2 variants). Thisproblem does not arise in the case of homozygous variants, for which itis obvious that the variants must be in trans (e.g., it is only an issuefor non-identical variants). All genome coordinates are based on hg19build.

In summary, Table 9 lists all unphased case-level compound heterozygousSNV solutions, which might represent further case-level solutions, werephasing to have been possible. Furthermore, it can be appreciated bythose skilled in the art that unphased solutions reported in Table 9 (2het SNVs per gene) or Table 10 (see below, which reports bet SNVs inpatients that also have a CNV reported in Table 1) can potentially causeor contribute to the patient's PML if follow up genetic analysis revealsthe pair of variants are on different alleles (e.g., each gene copyimpacted by a variant). Variants reported in Tables 1, 9, or 10 may alsobe found to be significantly deleterious on their own (e.g., infunctional studies on patient-derived cells, animal models, etc.) andthus constitute an AD model solution (e.g., genes presently listed as‘AR’ model in Table 6) may be causal or contributing to disease via anAD or AR model, like several genes already known to be AD or AR (Table6, ‘AD AR’ disease model).

TABLE 10 SNVs found in genes suspected of being impacted by acquiredCNVs Variant RefSeq Amino Frequency SEQ Sample Gene Variant Ref Alt AcidDetails ID ID Symbol Type Chr Position Allele Allele Change (Ethnicspecific) NO MVGS811- NR1P1 SNV het 21 16338814 T C N567S 0.00060 130113a MVGS995- VWA2 SNV het 10 116045796 G A V366M 0.02392 1173 4a PML01PKHD1 SNV het 6 51497503 C A R3842L 0.04707 1107 PML01 PKHD1 SNV het 651483961 T C Q4048R 0.49837 1104 PML02 DUSP16 ¹ SNV het 12 12673965 G AT23M 0.00015 1199 PML39 SALL2 SNV het 14 22004996 G T S13R 0.00231 1225PML51 JMY SNV het 5 78596018 G C D524H novel 1086 PML65 SALL2 SNV het 1421992397 T C S347G 0.07709 1223 ¹ The DUSP16 SNV (chr12: 12673965) wasin trans with a chr12 deletion of DUSP16 in this patient (PML02), whoseprimary diagnosis was lymphoma.

Table 10 is a list of all heterozygous SNVs that are potentiallycompound heterozygotes with a CNV on the allele. See text for a fullerexplanation. All genome coordinates are based on hg19 build.

TABLE 11 Key that maps Sample ID for the PML cases to the PML Case IDnumbers Sample ID PML Case ID MVGS1116-8a 3006 MVGS1359 3117 MVGS13683118 MVGS540-374b 3005 MVGS540-393b 3004 MVGS694-6a 3007 MVGS811-13a3009 MVGS995-4a 3010 PML01 3127 PML02 3126 PML03 3155 PML04 3156 PML053125 PML06 3124 PML09 3132 PML10 3157 PML12 3159 PML13 3160 PML14 3161PML15 3194 PML16 3163 PML17 3140 PML18 3141 PML19 3164 PML20 3143 PML213144 PML22 3145 PML23 3165 PML25 3166 PML26 3167 PML27 3168 PML28 3151PML29 3152 PML30 3153 PML31 3154 PML32 3169 PML33 3170 PML35 3171 PML363172 PML37 3173 PML38 3174 PML39 3175 PML40 3273 PML41 3177 PML43 3178PML44 3179 PML45 3180 PML46 3196 PML48 3197 PML49 3183 PML50 3198 PML513185 PML52 3186 PML53 3187 PML54 3188 PML55 3189 PML56 3190 PML57 3191PML58 3192 PML59 3193 PML60 3199 PML61 3200 PML62 3201 PML63 3202 PML643203 PML65 3204 PML66 3205 PML67 3277 PML68 3278 PML69 3279 PML72 3282PML70 control 3280 PML71 control 3281 PML73 control 3283 PML74 control3284 PML75 control 3285 PML76 control 3286

Table 11 provides the Sample ID and PML Case ID (experimental ID for CGHdata) for 77 PML cases' (includes 6 non-PML HIV cases listed ascontrols).

TABLE 12 Non-redundant list of transcript variants that correspond tothe set of genes that no CNV ‘solutions’ have been reported in the 71PML cases RefSeq RefSeq Gene Accession SEQ Symbol Number mRNADescription ID ACADM NM 000016 Homo sapiens acyl-CoA dehydrogenase, C-4to C-12 straight chain 1500 (ACADM), transcript variant 1, mRNA. ACADMNM 001127328 Homo sapiens atypical chemokine receptor 1 (Duffy bloodgroup) 1501 (ACKR1), transcript variant 1, mRNA. ACKRI NM 002036 Homosapiens atypical chemokine receptor 1 (Duffy blood group) 1502 (ACKR1),transcript variant 2, mRNA. ACKR1 NM 001122951 Homo sapiens atypicalchemokine receptor 1 isoform a 1503 ACP5 NM 001611 Homo sapiens acidphosphatase 5, tartrate resistant (ACP5), transcript 1504 variant 4,mRNA. ACP5 NM 001111034 Homo sapiens acid phosphatase 5, tartrateresistant (ACP5), transcript 1505 variant 2, mRNA. ACP5 NM 001111035Homo sapiens acid phosphatase 5, tartrate resistant (ACP5), transcript1506 variant 1, mRNA. ACP5 NM 001111036 Homo sapiens acid phosphatase 5,tartrate resistant (ACP5), transcript 1507 variant 3, mRNA. ADAR NM001111 Homo sapiens adenosine deaminase, RNA-specific (ADAR), transcript1508 variant 1, mRNA. ADAR NM 015840 Homo sapiens adenosine deaminase,RNA-specific (ADAR), transcript 1509 variant 2, mRNA. ADAR NM 015841Homo sapiens adenosine deaminase, RNA-specific (ADAR), transcript 1510variant 3, mRNA. ADAR NM 001025107 Homo sapiens adenosine deaminase,RNA-specific (ADAR), transcript 1511 variant 4, mRNA. ADAR NM 001193495Homo sapiens adenosine deaminase, RNA-specific (ADAR), transcript 1512variant 5, mRNA. ADK NM 001202450 Homo sapiens adenosine kinase (ADK),transcript variant 4, mRNA. 1513 ADK NM 006721 Homo sapiens adenosinekinase (ADK), transcript variant 2, mRNA. 1514 ADK NM 001123 Homosapiens adenosine kinase (ADK), transcript variant 1, mRNA. 1515 ADK NM001202449 Homo sapiens adenosine kinase (ADK), transcript variant 3,mRNA. 1516 AICDA NM 020661 Homo sapiens activation-induced cytidinedeaminase (AICDA), mRNA. 1517 AK2 NM 001199199 Homo sapiens adenylatekinase 2 (AK2), transcript variant 3, mRNA. 1518 AK2 NM 013411 Homosapiens adenylate kinase 2 (AK2), transcript variant 2, mRNA. 1519 AK2NM 001625 Homo sapiens adenylate kinase 2 (AK2), transcript variant 1,mRNA. 1520 ALG12 NM 024105 Homo sapiens ALG12,alpha-1,6-mannosyltransferase (ALG12), 1521 mRNA. ALPL NM 000478 Homosapiens alkaline phosphatase, liver/bone/kidney (ALPL), 1522 transcriptvariant 1, mRNA. ALPL NM 001127501 Homo sapiens alkaline phosphatase,liver/bone/kidney (ALPL), 1523 transcript variant 2, mRNA. ALPL NM001177520 Homo sapiens alkaline phosphatase, liver/bone/kidney (ALPL),1524 transcript variant 3, mRNA. AP3B1 NM 001271769 Homo sapiens adaptorrelated protein complex 3 beta 1 subunit 1525 (AP3B1), transcriptvariant 2, mRNA. AP3B1 NM 003664 Homo sapiens adaptor related proteincomplex 3 beta 1 subunit 1526 (AP3B1), transcript variant 1, mRNA. AP3B2NM 004644 Homo sapiens adaptor-related protein complex 3, beta 2 subunit1527 (AP3B2), transcript variant 2, mRNA. AP3D1 NM 003938 Homo sapiensadaptor-related protein complex 3, delta 1 subunit 1528 (AP3D1),transcript variant 2, mRNA. AP3D1 NM 001261826 Homo sapiensadaptor-related protein complex 3, delta 1 subunit 1529 (AP3D1),transcript variant 3, mRNA. APOLI NM 001136540 Homo sapiensapolipoprotein L1 (APOL1), transcript variant 3, mRNA. 1530 APOLI NM001136541 Homo sapiens apolipoprotein L1 (APOL1), transcript variant 4,mRNA. 1531 APOL1 NM 003661 Homo sapiens apolipoprotein L1 (APOL1),transcript variant 1, mRNA. 1532 APOL1 NM 145343 Homo sapiensapolipoprotein L1 (APOL1), transcript variant 2, mRNA. 1533 ASHIL NM018489 Homo sapiens ASH1 like histone lysine methyltransferase (ASH1L),1534 mRNA. ATL2 NM 001135673 Homo sapiens atlastin GTPase 2 (ATL2),transcript variant 2, mRNA. 1535 ATL2 NM 022374 Homo sapiens atlastinGTPase 2 (ATL2), transcript variant 1, mRNA. 1536 ATL2 NR 024191 Homosapiens atlastin GTPase 2 (ATL2), transcript variant 3, non- 1537 codingRNA. ATM NM 000051 Homo sapiens ATM serine/threonine kinase (ATM), mRNA.1538 ATR NM 001184 Homo sapiens ATR serine/threonine kinase (ATR), mRNA.1539 BACH2 NM 001170794 Homo sapiens BTB domain and CNC homolog 2(BACH2), transcript 1540 variant 2, mRNA. BACH2 NM 021813 Homo sapiensBTB domain and CNC homolog 2 (BACH2), transcript 1541 variant 1, mRNA.BAG3 NM 004281 Homo sapiens BCL2 associated athanogene 3 (BAG3), mRNA.1542 BCL10 NM 003921 Homo sapiens B-cell CLL/lymphoma 10 (BCL10),transcript variant 1, 1543 mRNA BLM NM 000057 Homo sapiens Bloomsyndrome RecQ like helicase (BLM), transcript 1544 variant 1, mRNA. BLNKNM 001114094 Homo sapiens B-cell linker (BLNK), transcript variant 2,mRNA. 1545 BLNK NM 001258440 Homo sapiens B-cell linker (BLNK),transcript variant 3, mRNA. 1546 BLNK NM 001258441 Homo sapiens B-celllinker (BLNK), transcript variant 4, mRNA. 1547 BLNK NM 001258442 Homosapiens B-cell linker (BLNK), transcript variant 5, mRNA. 1548 BLNK NM013314 Homo sapiens B-cell linker (BLNK), transcript variant 1, mRNA.1549 BLNK NR 047680 Homo sapiens B-cell linker (BLNK), transcriptvariant 6, non-coding 1550 RNA. BLNK NR 047681 Homo sapiens B-celllinker (BLNK), transcript variant 7, non-coding 1551 RNA. BLNK NR 047682Homo sapiens B-cell linker (BLNK), transcript variant 8, non-coding 1552RNA. BLNK NR 047683 Homo sapiens B-cell linker (BLNK), transcriptvariant 9, non-coding 1553 RNA. BLOC1S6 NM 012388 Homo sapiensbiogenesis of lysosomal organelles complex 1 subunit 6 1554 (BLOCIS6),transcript variant 2, mRNA. BTK NM 000061 Homo sapiens Bruton tyrosinekinase (BTK), transcript variant 1, 1555 mRNA. C11orf65 NM 152587 Homosapiens chromosome 11 open reading frame 65 (C11orf65), 1556 mRNA. C1QANM 015991 Homo sapiens complement component 1, q subcomponent, A chain1557 (C1QA), mRNA. C1QB NM 000491 Homo sapiens complement component 1, qsubcomponent, B chain 1558 (C1QB), mRNA. C1QC NM 001114101 Homo sapienscomplement component 1, q subcomponent, C chain 1559 (C1QC), transcriptvariant 1, mRNA. C1QC NM 172369 Homo sapiens complement component 1, qsubcomponent, C chain 1560 (C1QC), transcript variant 2, mRNA. C5AR1 NM001736 Homo sapiens complement component 5a receptor 1 (CSAR1), mRNA.1561 CARD11 NM 032415 Homo sapiens caspase recruitment domain familymember 11 1562 (CARD11), transcript variant 2, mRNA. CARD9 NM 052813Homo sapiens caspase recruitment domain family, member 9 (CARD9), 1563transcript variant 1, mRNA. CARD9 NM 052814 Homo sapiens caspaserecruitment domain family, member 9 (CARD9), 1564 transcript variant 2,mRNA. CASP8 NM 001080124 Homo sapiens caspase 8 (CASP8), transcriptvariant F, mRNA. 1565 CASP8 NM 001228 Homo sapiens caspase 8 (CASP8),transcript variant A, mRNA. 1566 CASP8 NM 033355 Homo sapiens caspase 8(CASP8), transcript variant B, mRNA. 1567 CASP8 NM 033358 Homo sapienscaspase 8 (CASP8), transcript variant E, mRNA. 1568 CASP8 NM 001080125Homo sapiens caspase 8 (CASP8), transcript variant G, mRNA. 1569 CASP8NM 033356 Homo sapiens caspase 8 (CASP8), transcript variant C, mRNA.1570 CCL11 NM 002986 Homo sapiens C-C motif chemokine ligand 11 (CCL11),mRNA. 1571 CCL2 NM 002982 Homo sapiens C-C motif chemokine ligand 2(CCL2), mRNA. 1572 CCL5 NM 002985 Homo sapiens C-C motif chemokineligand 5 (CCL5), transcript variant 1573 1, mRNA. CCR2 NM 001123041 Homosapiens C-C motif chemokine receptor 2 (CCR2), transcript 1574 variantA, mRNA. CCR2 NM 001123396 Homo sapiens C-C motif chemokine receptor 2(CCR2), transcript 1575 variant B, mRNA. CCR5 NM 000579 Homo sapiens C-Cmotif chemokine receptor 5 (gene/pseudogene) 1576 (CCR5), transcriptvariant A, mRNA. CCR5 NM 001100168 Homo sapiens C-C motif chemokinereceptor 5 (gene/pseudogene) 1577 (CCR5), transcript variant B, mRNA.CD180 NM 005582 Homo sapiens CD180 molecule (CD180), mRNA. 1578 CD19 NM001178098 Homo sapiens CD19 molecule (CD19), transcript variant 1, mRNA.1579 CD19 NM 001770 Homo sapiens CD19 molecule (CD19), transcriptvariant 2, mRNA. 1580 CD209 NM 001144893 Homo sapiens CD209 molecule(CD209), transcript variant 5, mRNA. 1581 CD209 NM 001144894 Homosapiens CD209 molecule (CD209), transcript variant 6, mRNA. 1582 CD209NM 001144895 Homo sapiens CD209 molecule (CD209), transcript variant 7,mRNA. 1583 CD209 NM 001144896 Homo sapiens CD209 molecule (CD209),transcript variant 3, mRNA. 1584 CD209 NM 001144897 Homo sapiens CD209molecule (CD209), transcript variant 4, mRNA. 1585 CD209 NM 001144899Homo sapiens CD209 molecule (CD209), transcript variant 8, mRNA. 1586CD209 NM 021155 Homo sapiens CD209 molecule (CD209), transcript variant1, mRNA. 1587 CD209 NR 026692 Homo sapiens CD209 molecule (CD209),transcript variant 2, non- 1588 coding RNA. CD247 NM 000734 Homo sapiensCD247 molecule (CD247), transcript variant 2, mRNA. 1589 CD247 NM 198053Homo sapiens CD247 molecule (CD247), transcript variant 1, mRNA. 1590CD27 NM 001242 Homo sapiens CD27 molecule (CD27), mRNA. 1591 CD27- NR015382 Homo sapiens CD27 antisense RNA 1 (CD27-AS1), long non-coding1592 AS1 RNA. CD34 NM 001025109 Homo sapiens CD34 molecule (CD34),transcript variant 1, mRNA. 1593 CD34 NM 001773 Homo sapiens CD34molecule (CD34), transcript variant 2, mRNA. 1594 CD3D NM 000732 Homosapiens CD3d molecule (CD3D), transcript variant 1, mRNA. 1595 CD3D NM001040651 Homo sapiens CD3d molecule (CD3D), transcript variant 2, mRNA.1596 CD3E NM 000733 Homo sapiens CD3e molecule (CD3E), mRNA. 1597 CD3GNM 000073 Homo sapiens CD3g molecule (CD3G), mRNA. 1598 CD40 NM 001250Homo sapiens CD40 molecule (CD40), transcript variant 1, mRNA. 1599 CD40NM 152854 Homo sapiens CD40 molecule (CD40), transcript variant 2, mRNA.1600 CD40LG NM 000074 Homo sapiens CD40 ligand (CD40LG), mRNA. 1601 CD55NM 000574 Homo sapiens CD55 molecule (Cromer blood group) (CD55),transcript 1602 variant 1, mRNA. CD55 NM 001114752 Homo sapiens CD55molecule (Cromer blood group) (CD55), transcript 1603 variant 2, mRNA.CD59 NM 000611 Homo sapiens CD59 molecule (CD59), transcript variant 2,mRNA. 1604 CD59 NM 001127223 Homo sapiens CD59 molecule (CD59),transcript variant 5, mRNA. 1605 CD59 NM 001127225 Homo sapiens CD59molecule (CD59), transcript variant 6, mRNA. 1606 CD59 NM 001127226 Homosapiens CD59 molecule (CD59), transcript variant 7, mRNA. 1607 CD59 NM001127227 Homo sapiens CD59 molecule (CD59), transcript variant 8, mRNA.1608 CD59 NM 203329 Homo sapiens CD59 molecule (CD59), transcriptvariant 3, mRNA. 1609 CD59 NM 203330 Homo sapiens CD59 molecule (CD59),transcript variant 1, mRNA. 1610 CD59 NM 203331 Homo sapiens CD59molecule (CD59), transcript variant 4, mRNA. 1611 CD79A NM 001783 Homosapiens CD79a molecule (CD79A), transcript variant 1, mRNA. 1612 CD79ANM 021601 Homo sapiens CD79a molecule (CD79A), transcript variant 2,mRNA. 1613 CD79B NM 000626 Homo sapiens CD79b molecule (CD79B),transcript variant 1, mRNA. 1614 CD79B NM 001039933 Homo sapiens CD79bmolecule (CD79B), transcript variant 3, mRNA. 1615 CD79B NM 021602 Homosapiens CD79b molecule (CD79B), transcript variant 2, mRNA. 1616 CD81 NM004356 Homo sapiens CD81 molecule (CD81), transcript variant 1, mRNA.1617 CD8A NM 001145873 Homo sapiens CD8a molecule (CD8A), transcriptvariant 3, mRNA. 1618 CD8A NM 001768 Homo sapiens CD8a molecule (CD8A),transcript variant 1, mRNA. 1619 CD8A NM 171827 Homo sapiens CD8amolecule (CD8A), transcript variant 2, mRNA. 1620 CD8A NR 027353 Homosapiens CD8a molecule (CD8A), transcript variant 4, non-coding 1621 RNA.CDCA7 NM 031942 Homo sapiens cell division cycle associated 7 (CDCA7),transcript 1622 variant 1, mRNA. CDCA7 NM 145810 Homo sapiens celldivision cycle associated 7 (CDCA7), transcript 1623 variant 2, mRNA.CEBPB NM 005194 Homo sapiens CCAAT/enhancer binding protein beta(CEBPB), 1624 transcript variant 1, mRNA. CHD7 NM 017780 Homo sapienschromodomain helicase DNA binding protein 7 (CHD7), 1625 transcriptvariant 1, mRNA. CHEK1 NM 001114121 Homo sapiens checkpoint kinase 1(CHEK1), transcript variant 2, 1626 mRNA. CHEK1 NM 001114122 Homosapiens checkpoint kinase 1 (CHEK1), transcript variant 1, 1627 mRNA.CHEK1 NM 001244846 Homo sapiens checkpoint kinase 1 (CHEK1), transcriptvariant 4, 1628 mRNA. CHEK1 NR 045204 Homo sapiens checkpoint kinase 1(CHEK1), transcript variant 5, non- 1629 coding RNA. CHEK1 NR 045205Homo sapiens checkpoint kinase 1 (CHEK1), transcript variant 6, non-1630 coding RNA. CHEK1 NM 001274 Homo sapiens checkpoint kinase 1(CHEK1), transcript variant 3, 1631 mRNA. CIITA NM 000246 Homo sapiensclass II major histocompatibility complex transactivator 1632 (CIITA),transcript variant 2, mRNA. CLCN7 NM 001114331 Homo sapiens chloridechannel, voltage-sensitive 7 (CLCN7), transcript 1633 variant 2, mRNA.CLCN7 NM 001287 Homo sapiens chloride channel, voltage-sensitive 7(CLCN7), transcript 1634 variant 1, mRNA. COG6 NM 001145079 Homo sapienscomponent of oligomeric golgi complex 6 (COG6), 1635 transcript variant2, mRNA. COG6 NM 020751 Homo sapiens component of oligomeric golgicomplex 6 (COG6), 1636 transcript variant 1, mRNA. COG6 NR 026745 Homosapiens component of oligomeric golgi complex 6 (COG6), 1637 transcriptvariant 3, non-coding RNA. CORO1A NM 001193333 Homo sapiens coronin 1A(CORO1A), transcript variant 1, mRNA. 1638 COROIA NM 007074 Homo sapienscoronin 1A (COROIA), transcript variant 2, mRNA. 1639 CR2 NM 001006658Homo sapiens complement component 3d receptor 2 (CR2), transcript 1640variant 1, mRNA. CR2 NM 001877 Homo sapiens complement component 3dreceptor 2 (CR2), transcript 1641 variant 2, mRNA. CRTC3 NM 001042574Homo sapiens CREB regulated transcription coactivator 3 (CRTC3), 1642transcript variant 2, mRNA. CRTC3 NM 022769 Homo sapiens CREB regulatedtranscription coactivator 3 (CRTC3), 1643 transcript variant 1, mRNA.CSF3R NM 000760 Homo sapiens colony stimulating factor 3 receptor(granulocyte) 1644 (CSF3R), transcript variant 1, mRNA. CSF3R NM 156039Homo sapiens colony stimulating factor 3 receptor (granulocyte) 1645(CSF3R), transcript variant 3, mRNA. CSF3R NM 172313 Homo sapiens colonystimulating factor 3 receptor (granulocyte) 1646 (CSF3R), transcriptvariant 4, mRNA. CTLA4 NM 005214 Homo sapiens cytotoxicT-lymphocyte-associated protein 4 (CTLA4), 1647 transcript variant 1,mRNA. CTLA4 NM 001037631 Homo sapiens cytotoxic T-lymphocyte-associatedprotein 4 (CTLA4), 1648 transcript variant 2, mRNA. CTPS1 NM 001905 Homosapiens CTP synthase 1 (CTPS1), transcript variant 1, mRNA. 1649 CTSC NM148170 Homo sapiens cathepsin C (CTSC), transcript variant 2, mRNA. 1650CTSC NM 001114173 Homo sapiens cathepsin C (CTSC), transcript variant 3,mRNA. 1651 CTSC NM 001814 Homo sapiens cathepsin C (CTSC), transcriptvariant 1, mRNA. 1652 CX3CR1 NM 001171171 Homo sapiens C-X3-C motifchemokine receptor 1 (CX3CR1), 1653 transcript variant 2, mRNA. CX3CR1NM 001171172 Homo sapiens C-X3-C motif chemokine receptor 1 (CX3CR1),1654 transcript variant 3, mRNA. CX3CR1 NM 001171174 Homo sapiens C-X3-Cmotif chemokine receptor 1 (CX3CR1), 1655 transcript variant 1, mRNA.CX3CR1 NM 001337 Homo sapiens C-X3-C motif chemokine receptor 1(CX3CR1), 1656 transcript variant 4, mRNA. CXCL12 NM 000609 Homo sapiensC-X-C motif chemokine ligand 12 (CXCL12), transcript 1657 variant 2,mRNA. CXCL12 NM 001033886 Homo sapiens C-X-C motif chemokine ligand 12(CXCL12), transcript 1658 variant 3, mRNA. CXCL12 NM 001178134 Homosapiens C-X-C motif chemokine ligand 12 (CXCL12), transcript 1659variant 4, mRNA. CXCL12 NM 199168 Homo sapiens C-X-C motif chemokineligand 12 (CXCL12), transcript 1660 variant 1, mRNA. CXCL9 NM 002416Homo sapiens C-X-C motif chemokine ligand 9 (CXCL9), mRNA. 1661 CXCR1 NM000634 Homo sapiens C-X-C motif chemokine receptor 1 (CXCR1), mRNA. 1662CXCR4 NM 001008540 Homo sapiens C-X-C motif chemokine receptor 4(CXCR4), transcript 1663 variant 1, mRNA. CXCR4 NM 003467 Homo sapiensC-X-C motif chemokine receptor 4 (CXCR4), transcript 1664 variant 2,mRNA. CXorf40A NM 001171907 Homo sapiens chromosome X open reading frame40A (CXorf40A), 1665 transcript variant 2, mRNA. CXorf40A NM 001171908Homo sapiens chromosome X open reading frame 40A (CXorf40A), 1666transcript variant 3, mRNA. CXorf40A NM 178124 Homo sapiens chromosome Xopen reading frame 40A (CXorf40A), 1667 transcript variant 1, mRNA.CXorf40A NM 001171909 Homo sapiens chromosome X open reading frame 40A(CXorf40A), 1668 transcript variant 4, mRNA. CYBB NM 000397 Homo sapienscytochrome b-245, beta polypeptide (CYBB), mRNA. 1669 CYP2SI NM 030622Homo sapiens cytochrome P450 family 2 subfamily S member 1 1670(CYP2S1), mRNA. DCLRE1C NM 001033855 Homo sapiens DNA cross-link repair1C (DCLRE1C), transcript variant 1671 a, mRNA DCLRE1C NM 001033857 Homosapiens DNA cross-link repair 1C (DCLRE1C), transcript variant 1672 d,mRNA. DCLRE1C NM 001033858 Homo sapiens DNA cross-link repair 1C(DCLRE1C), transcript variant 1673 c, mRNA. DCLRE1C NM 022487 Homosapiens DNA cross-link repair 1C (DCLRE1C), transcript variant 1674 b,mRNA. DDX1 NM 004939 Homo sapiens DEAD/H-box helicase 1 (DDX1), mRNA.1675 DDX58 NM 014314 Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide58 1676 (DDX58), mRNA. DHX58 NM 024119 Homo sapiens DEXH (Asp-Glu-X-His)box polypeptide 58 (DHX58), 1677 mRNA. DKC1 NM 001142463 Homo sapiensdyskerin pseudouridine synthase 1 (DKC1), transcript 1678 variant 2,mRNA. DKC1 NM 001363 Homo sapiens dyskerin pseudouridine synthase 1(DKC1), transcript 1679 variant 1, mRNA. DNMT3B NM 001207055 Homosapiens DNA methyltransferase 3 beta (DNMT3B), transcript 1680 variant7, mRNA. DNMT3B NM 001207056 Homo sapiens DNA methyltransferase 3 beta(DNMT3B), transcript 1681 variant 8, mRNA. DNMT3B NM 006892 Homo sapiensDNA methyltransferase 3 beta (DNMT3B), transcript 1682 variant 1, mRNA.DNMT3B NM 175848 Homo sapiens DNA methyltransferase 3 beta (DNMT3B),transcript 1683 variant 2, mRNA. DNMT3B NM 175849 Homo sapiens DNAmethyltransferase 3 beta (DNMT3B), transcript 1684 variant 3, mRNA.DNMT3B NM 175850 Homo sapiens DNA methyltransferase 3 beta (DNMT3B),transcript 1685 variant 6, mRNA. DOCK2 NM 004946 Homo sapiens dedicatorof cytokinesis 2 (DOCK2), mRNA. 1686 DOCK8 NM 203447 Homo sapiensdedicator of cytokinesis 8 (DOCK8), transcript variant 1, 1687 mRNA.DOCK8 NM 001190458 Homo sapiens dedicator of cytokinesis 8 (DOCK8),transcript variant 2, 1688 mRNA. DOCK8 NM 001193536 Homo sapiensdedicator of cytokinesis 8 (DOCK8), transcript variant 3, 1689 mRNA.DSC1 NM 004948 Homo sapiens desmocollin 1 (DSC1), transcript variantDsc1b, mRNA. 1690 DSC1 NM 024421 Homo sapiens desmocollin 1 (DSC1),transcript variant Dsc1a, mRNA. 1691 EGR1 NM 001964 Homo sapiens earlygrowth response 1 (EGR1), mRNA. 1692 ELANE NM 001972 Homo sapienselastase, neutrophil expressed (ELANE), mRNA. 1693 EPG5 NM 020964 Homosapiens ectopic P-granules autophagy protein 5 homolog (EPG5), 1694mRNA. ETF1 NM 004730 Homo sapiens eukaryotic translation terminationfactor 1 (ETF1), 1695 transcript variant 1, mRNA. F9 NM 000133 Homosapiens coagulation factor IX (F9), transcript variant 1, mRNA. 1696 FASNM 000043 Homo sapiens Fas cell surface death receptor (FAS), transcriptvariant 1697 1, mRNA. FAS NM 152871 Homo sapiens Fas cell surface deathreceptor (FAS), transcript variant 1698 2, mRNA. FAS NM 152872 Homosapiens Fas cell surface death receptor (FAS), transcript variant 16993, mRNA. FAS NR 028033 Homo sapiens Fas cell surface death receptor(FAS), transcript variant 1700 4, non-coding RNA. FAS NR 028034 Homosapiens Fas cell surface death receptor (FAS), transcript variant 17015, non-coding RNA. FAS NR 028035 Homo sapiens Fas cell surface deathreceptor (FAS), transcript variant 1702 6, non-coding RNA. FAS NR 028036Homo sapiens Fas cell surface death receptor (FAS), transcript variant1703 7, non-coding RNA. FASLG NM 000639 Homo sapiens Fas ligand (TNFsuperfamily, member 6) (FASLG), 1704 mRNA. FCGR2A NM 001136219 Homosapiens Fc fragment of IgG receptor IIa (FCGR2A), transcript 1705variant 1, mRNA. FCGR2A NM 021642 Homo sapiens Fc fragment of IgGreceptor IIa (FCGR2A), transcript 1706 variant 2, mRNA. FCGR3A NM 000569Homo sapiens Fc fragment of IgG receptor IIIa (FCGR3A), transcript 1707variant 1, mRNA. FCGR3A NM 001127592 Homo sapiens Fc fragment of IgGreceptor IIIa (FCGR3A), transcript 1708 variant 2, mRNA. FCGR3A NM001127593 Homo sapiens Fc fragment of IgG receptor IIIa (FCGR3A),transcript 1709 variant 3, mRNA. FCGR3A NM 001127595 Homo sapiens Fcfragment of IgG receptor IIIa (FCGR3A), transcript 1710 variant 4, mRNA.FCGR3A NM 001127596 Homo sapiens Fc fragment of IgG receptor IIIa(FCGR3A), transcript 1711 variant 5, mRNA. FCN3 NM 003665 Homo sapiensficolin 3 (FCN3), transcript variant 1, mRNA. 1712 FCN3 NM 173452 Homosapiens ficolin 3 (FCN3), transcript variant 2, mRNA. 1713 FEZ1 NM005103 Homo sapiens fasciculation and elongation protein zeta 1 (FEZ1),1714 transcript variant 1, mRNA. FEZ1 NM 022549 Homo sapiensfasciculation and elongation protein zeta 1 (FEZ1), 1715 transcriptvariant 2, mRNA. FOS NM 005252 Homo sapiens Fos proto-oncogene, AP-1transcription factor subunit 1716 (FOS), mRNA. FOXH1 NM 003923 Homosapiens forkhead box H1 (FOXH1), mRNA. 1717 FOXN1 NM 003593 Homo sapiensforkhead box N1 (FOXN1), mRNA. 1718 FOXP3 NM 001114377 Homo sapiensforkhead box P3 (FOXP3), transcript variant 2, mRNA. 1719 FOXP3 NM014009 Homo sapiens forkhead box P3 (FOXP3), transcript variant 1, mRNA.1720 FPR1 NM 001193306 Homo sapiens formyl peptide receptor 1 (FPR1),transcript variant 1, 1721 mRNA. FPR1 NM 002029 Homo sapiens formylpeptide receptor 1 (FPR1), transcript variant 2, 1722 mRNA. G6PC3 NM138387 Homo sapiens glucose 6 phosphatase, catalytic, 3 (G6PC3),transcript 1723 variant 1, mRNA. G6PC3 NR 028582 Homo sapiens glucose 6phosphatase, catalytic, 3 (G6PC3), transcript 1724 variant 2, non-codingRNA. G6PC3 NR 028581 Homo sapiens glucose 6 phosphatase, catalytic, 3(G6PC3), transcript 1725 variant 3, non-coding RNA. GATA2 NM 001145661Homo sapiens GATA binding protein 2 (GATA2), transcript variant 1, 1726mRNA. GATA2 NM 001145662 Homo sapiens GATA binding protein 2 (GATA2),transcript variant 3, 1727 mRNA. GATA2 NM 032638 Homo sapiens GATAbinding protein 2 (GATA2), transcript variant 2, 1728 mRNA. GFI1 NM005263 Homo sapiens growth factor independent 1 transcription repressor1729 (GFI1), transcript variant 1, mRNA. GFI1 NM 001127215 Homo sapiensgrowth factor independent 1 transcription repressor 1730 (GFII),transcript variant 2, mRNA. GFI1 NM 001127216 Homo sapiens growth factorindependent I transcription repressor 1731 (GFI1), transcript variant 3,mRNA. GOLGB1 NM 001256486 Homo sapiens golgin B1 (GOLGB1), transcriptvariant 1, mRNA. 1732 GOLGB1 NM 001256487 Homo sapiens golgin B1(GOLGB1), transcript variant 3, mRNA. 1733 GOLGB1 NM 001256488 Homosapiens golgin B1 (GOLGB1), transcript variant 4, mRNA. 1734 GOLGB1 NM004487 Homo sapiens golgin B1 (GOLGB1), transcript variant 2, mRNA. 1735GPRC5A NM 003979 Homo sapiens G protein-coupled receptor class C group 5member A 1736 (GPRC5A), mRNA. GRAP2 NM 004810 Homo sapiens GRB2-relatedadaptor protein 2 (GRAP2), mRNA. 1737 HAX1 NM 006118 Homo sapiens HCLS1associated protein X-1 (HAX1), transcript 1738 variant 1, mRNA. HAX1 NM001018837 Homo sapiens HCLS1 associated protein X-1 (HAX1), transcript1739 variant 2, mRNA. HELLS NM 018063 Homo sapiens helicase,lymphoid-specific (HELLS), transcript variant 1740 1, mRNA. HIVEP1 NM002114 Homo sapiens human immunodeficiency virus type I enhancer binding1741 protein 1 (HIVEP1), mRNA. HIVEP2 NM 006734 Homo sapiens humanimmunodeficiency virus type I enhancer binding 1742 protein 2 (HIVEP2),mRNA. HIVEP3 NM 001127714 Homo sapiens human immunodeficiency virus typeI enhancer binding 1743 protein 3 (HIVEP3), transcript variant 2, mRNA.HIVEP3 NM 024503 Homo sapiens human immunodeficiency virus type Ienhancer binding 1744 protein 3 (HIVEP3), transcript variant 1, mRNA.HIVEP3 NR 038260 Homo sapiens human immunodeficiency virus type Ienhancer binding 1745 protein 3 (HIVEP3), transcript variant 3,non-coding RNA. HIVEP3 NR 038261 Homo sapiens human immunodeficiencyvirus type I enhancer binding 1746 protein 3 (HIVEP3), transcriptvariant 4, non-coding RNA. HP NM 001126102 Homo sapiens haptoglobin(HP), transcript variant 2, mRNA. 1747 HP NM 005143 Homo sapienshaptoglobin (HP), transcript variant 1, mRNA. 1748 HPCAL1 NM 002149 Homosapiens hippocalcin like 1 (HPCAL1), transcript variant 1, 1749 mRNA.HPCAL1 NM 134421 Homo sapiens hippocalcin like 1 (HPCAL1), transcriptvariant 2, 1750 mRNA. HPCAL1 NM 001258357 Homo sapiens hippocalcin like1 (HPCAL1), transcript variant 3, 1751 mRNA. HPCAL1 NM 001258358 Homosapiens hippocalcin like 1 (HPCAL1), transcript variant 4, 1752 mRNA.HPCAL1 NM 001258359 Homo sapiens hippocalcin like 1 (HPCAL1), transcriptvariant 5, 1753 mRNA. HTR2A NM 000621 Homo sapiens 5-hydroxytryptaminereceptor 2A (HTR2A), transcript 1754 variant 1, mRNA. HTR2A NM 001165947Homo sapiens 5-hydroxytryptamine (serotonin) receptor 2A, G protein-1755 coupled (HTR2A), transcript variant 2, mRNA. ICOS NM 012092 Homosapiens inducible T-cell costimulator (ICOS), mRNA. 1756 IDI1 NM 004508Homo sapiens isopentenyl-diphosphate delta isomerase 1 (IDI1), 1757transcript variant 1, mRNA. IFIH1 NM 022168 Homo sapiens interferoninduced with helicase C domain 1 (IFIH1), 1758 mRNA. IFNAR1 NM 000629Homo sapiens interferon (alpha, beta and omega) receptor 1 (IFNAR1),1759 mRNA. IFNAR2 NM 207584 Homo sapiens interferon (alpha, beta andomega) receptor 2 (IFNAR2), 1760 transcript variant 3, mRNA. IFNAR2 NM207585 Homo sapiens interferon (alpha, beta and omega) receptor 2(IFNAR2), 1761 transcript variant 1, mRNA. IFNAR2 NM 000874 Homo sapiensinterferon (alpha, beta and omega) receptor 2 (IFNAR2), 1762 transcriptvariant 2, mRNA. IFNG NM 000619 Homo sapiens interferon gamma (IFNG),mRNA. 1763 IFNGR1 NM 000416 Homo sapiens interferon gamma receptor 1(IFNGR1), mRNA. 1764 IFNGR2 NM 005534 Homo sapiens interferon gammareceptor 2 (interferon gamma 1765 transducer 1) (IFNGR2), transcriptvariant 2, mRNA. IGLL1 NM 020070 Homo sapiens immunoglobulin lambda likepolypeptide 1 (IGLL1), 1766 transcript variant 1, mRNA. IGLL1 NM 152855Homo sapiens immunoglobulin lambda like polypeptide 1 (IGLL1), 1767transcript variant 2, mRNA. IKBKB NM 001190720 Homo sapiens inhibitor ofkappa light polypeptide gene enhancer in B- 1768 cells, kinase beta(IKBKB), transcript variant 2, mRNA. IKBKB NM 001242778 Homo sapiensinhibitor of kappa light polypeptide gene enhancer in B- 1769 cells,kinase beta (IKBKB), transcript variant 7, mRNA. IKBKB NM 001556 Homosapiens inhibitor of kappa light polypeptide gene enhancer in B- 1770cells, kinase beta (IKBKB), transcript variant 1, mRNA. IKBKB NR 033818Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-1771 cells, kinase beta (IKBKB), transcript variant 5, non-coding RNA.IKBKB NR 033819 Homo sapiens inhibitor of kappa light polypeptide geneenhancer in B- 1772 cells, kinase beta (IKBKB), transcript variant 6,non-coding RNA. IKBKB NR 040009 Homo sapiens inhibitor of kappa lightpolypeptide gene enhancer in B- 1773 cells, kinase beta (IKBKB),transcript variant 8, non-coding RNA. IKBKG NM 001099856 Homo sapiensinhibitor of kappa light polypeptide gene enhancer in B- 1774 cells,kinase gamma (IKBKG), transcript variant 2, mRNA. IKBKG NM 001099857Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-1775 cells, kinase gamma (IKBKG), transcript variant 1, mRNA. IKBKG NM001145255 Homo sapiens inhibitor of kappa light polypeptide geneenhancer in B- 1776 cells, kinase gamma (IKBKG), transcript variant 4,mRNA. IKBKG NM 003639 Homo sapiens inhibitor of kappa light polypeptidegene enhancer in B- 1777 cells, kinase gamma (IKBKG), transcript variant3, mRNA. IKZF NM 001220765 Homo sapiens IKAROS family zinc finger 1(IKZF1), transcript variant 1778 2, mRNA. IKZF1 NM 001220767 Homosapiens IKAROS family zinc finger 1 (IKZF1), transcript variant 1779 4,mRNA. IKZF1 NM 001220768 Homo sapiens IKAROS family zinc finger 1(IKZF1), transcript variant 1780 5, mRNA. IKZF1 NM 001220770 Homosapiens IKAROS family zinc finger 1 (IKZF1), transcript variant 1781 7,mRNA. IKZF1 NM 001220771 Homo sapiens IKAROS family zinc finger 1(IKZF1), transcript variant 1782 8, mRNA. IKZF1 NM 006060 Homo sapiensIKAROS family zinc finger 1 (IKZF1), transcript variant 1783 1, mRNA.IL10 NM 000572 Homo sapiens interleukin 10 (IL10), mRNA. 1784 IL10RA NM001558 Homo sapiens interleukin 10 receptor subunit alpha (IL10RA), 1785transcript variant 1, mRNA. IL10RA NR 026691 Homo sapiens interleukin 10receptor subunit alpha (IL10RA), 1786 transcript variant 2, non-codingRNA. IL10RB NM 000628 Homo sapiens interleukin 10 receptor subunit beta(IL10RB), mRNA. 1787 IL12B NM 002187 Homo sapiens interleukin 12B(IL12B), mRNA. 1788 IL12RB1 NM 005535 Homo sapiens interleukin 12receptor subunit beta 1 (IL12RB1), 1789 transcript variant 1, mRNA.IL12RB1 NM 153701 Homo sapiens interleukin 12 receptor subunit beta 1(IL12RB1), 1790 transcript variant 2, mRNA. IL17F NM 052872 Homo sapiensinterleukin 17F (IL17F), mRNA 1791 IL17RA NM 014339 Homo sapiensinterleukin 17 receptor A (IL17RA), transcript variant 1, 1792 mRNA.ILIB NM 000576 Homo sapiens interleukin 1, beta (IL1B), mRNA. 1793 IL21NM 001207006 Homo sapiens interleukin 21 (IL21), transcript variant 2,mRNA. 1794 IL21 NM 021803 Homo sapiens interleukin 21 (IL21), transcriptvariant 1, mRNA. 1795 IL21R NM 181078 Homo sapiens interleukin 21receptor (IL21R), transcript variant 2, 1796 mRNA. IL21R NM 181079 Homosapiens interleukin 21 receptor (IL21R), transcript variant 3, 1797mRNA. IL21R NM 021798 Homo sapiens interleukin 21 receptor (IL21R),transcript variant 1, 1798 mRNA. IL2RA NM 000417 Homo sapiensinterleukin 2 receptor, alpha (IL2RA), transcript variant 1799 1, mRNA.IL2RG NM 000206 Homo sapiens interleukin 2 receptor subunit gamma(IL2RG), mRNA. 1800 IL4R NM 000418 Homo sapiens interleukin 4 receptor(IL4R), transcript variant 1, 1801 mRNA. IL4R NM 001257406 Homo sapiensinterleukin 4 receptor (IL4R), transcript variant 3, 1802 mRNA. IL4R NM001257407 Homo sapiens interleukin 4 receptor (IL4R), transcript variant4, 1803 mRNA. IL4R NM 001257997 Homo sapiens interleukin 4 receptor(IL4R), transcript variant 5, 1804 mRNA. IL7 NM 000880 Homo sapiensinterleukin 7 (IL7), transcript variant 1, mRNA. 1805 IL7 NM 001199886Homo sapiens interleukin 7 (IL7), transcript variant 2, mRNA. 1806 IL7NM 001199887 Homo sapiens interleukin 7 (IL7), transcript variant 3,mRNA. 1807 IL7 NM 001199888 Homo sapiens interleukin 7 (IL7), transcriptvariant 4, mRNA. 1808 IL7R NM 002185 Homo sapiens interleukin 7 receptor(IL7R), transcript variant 1, 1809 mRNA. IRAK4 NM 001114182 Homo sapiensinterleukin 1 receptor associated kinase 4 (IRAK4), 1810 transcriptvariant 1, mRNA. IRAK4 NM 001145256 Homo sapiens interleukin 1 receptorassociated kinase 4 (IRAK4), 1811 transcript variant 3, mRNA. IRAK4 NM001145257 Homo sapiens interleukin 1 receptor associated kinase 4(IRAK4), 1812 transcript variant 4, mRNA. IRAK4 NM 001145258 Homosapiens interleukin 1 receptor associated kinase 4 (IRAK4), 1813transcript variant 5, mRNA. IRAK4 NM 016123 Homo sapiens interleukin 1receptor associated kinase 4 (IRAK4), 1814 transcript variant 2, mRNA.IRF3 NM 001197122 Homo sapiens interferon regulatory factor 3 (IRF3),transcript variant 2, 1815 mRNA. IRF3 NM 001197123 Homo sapiensinterferon regulatory factor 3 (IRF3), transcript variant 3, 1816 mRNA.IRF3 NM 001197124 Homo sapiens interferon regulatory factor 3 (IRF3),transcript variant 4, 1817 mRNA. IRF3 NM 001197125 Homo sapiensinterferon regulatory factor 3 (IRF3), transcript variant 5, 1818 mRNA.IRF3 NM 001197126 Homo sapiens interferon regulatory factor 3 (IRF3),transcript variant 6, 1819 mRNA. IRF3 NM 001197127 Homo sapiensinterferon regulatory factor 3 (IRF3), transcript variant 7, 1820 mRNA.IRF3 NM 001197128 Homo sapiens interferon regulatory factor 3 (IRF3),transcript variant 8, 1821 mRNA. IRF3 NM 001571 Homo sapiens interferonregulatory factor 3 (IRF3), transcript variant 1, 1822 mRNA. IRF3 NR045568 Homo sapiens interferon regulatory factor 3 (IRF3), transcriptvariant 9, 1823 non-coding RNA. IRF7 NM 001572 Homo sapiens interferonregulatory factor 7 (IRF7), transcript variant a, 1824 mRNA. IRF7 NM004029 Homo sapiens interferon regulatory factor 7 (IRF7), transcriptvariant b, 1825 mRNA. IRF7 NM 004031 Homo sapiens interferon regulatoryfactor 7 (IRF7), transcript variant d, 1826 mRNA. IRF8 NM 002163 Homosapiens interferon regulatory factor 8 (IRF8), mRNA. 1827 IRGM NM001145805 Homo sapiens immunity related GTPase M (IRGM), mRNA. 1828ISG15 NM 005101 Homo sapiens ISG15 ubiquitin-like modifier (ISG15),mRNA. 1829 ITK NM 005546 Homo sapiens IL2 inducible T-cell kinase (ITK),mRNA. 1830 ITSN2 NM 006277 Homo sapiens intersectin 2 (ITSN2),transcript variant 1, mRNA. 1831 ITSN2 NM 019595 Homo sapiensintersectin 2 (ITSN2), transcript variant 3, mRNA. 1832 ITSN2 NM 147152Homo sapiens intersectin 2 (ITSN2), transcript variant 2, mRNA. 1833JAGN1 NM 032492 Homo sapiens jagunal homolog 1 (Drosophila) (JAGNI),mRNA. 1834 JAK3 NM 000215 Homo sapiens Janus kinase 3 (JAK3), mRNA. 1835JMY NM 152405 Homo sapiens junction mediating and regulatory protein,p53 cofactor 1836 (JMY), mRNA. JUN NM 002228 Homo sapiens Junproto-oncogene, AP-1 transcription factor subunit 1837 (JUN), mRNA.KITLG NM 000899 Homo sapiens KIT ligand (KITLG), transcript variant b,mRNA. 1838 KITLG NM 003994 Homo sapiens KIT ligand (KITLG), transcriptvariant a, mRNA. 1839 LAMTOR2 NM 001145264 Homo sapiens lateendosomal/lysosomal adaptor, MAPK and MTOR 1840 activator 2 (LAMTOR2),transcript variant 2, mRNA. LAMTOR2 NM 014017 Homo sapiens lateendosomal/lysosomal adaptor, MAPK and MTOR 1841 activator 2 (LAMTOR2),transcript variant 1, mRNA. LCK NM 005356 Homo sapiens LCKproto-oncogene, Src family tyrosine kinase (LCK), 1842 transcriptvariant 2, mRNA. LCK NM 001042771 Homo sapiens LCK proto-oncogene, Srcfamily tyrosine kinase (LCK), 1843 transcript variant 1, mRNA. LCP2 NM005565 Homo sapiens lymphocyte cytosolic protein 2 (SH2 domaincontaining 1844 leukocyte protein of 76 kDa) (LCP2), mRNA. LIG1 NM000234 Homo sapiens DNA ligase 1 (LIG1), transcript variant 1, mRNA.1845 LIG4 NM 001098268 Homo sapiens DNA ligase 4 (LIG4), transcriptvariant 3, mRNA. 1846 LIG4 NM 002312 Homo sapiens DNA ligase 4 (LIG4),transcript variant 1, mRNA. 1847 LIG4 NM 206937 Homo sapiens DNA ligase4 (LIG4), transcript variant 2, mRNA. 1848 LRBA NM 001199282 Homosapiens LPS responsive beige-like anchor protein (LRBA), 1849 transcriptvariant 1, mRNA. LRBA NM 006726 Homo sapiens LPS responsive beige-likeanchor protein (LRBA), 1850 transcript variant 2, mRNA. LYST NM 000081Homo sapiens lysosomal trafficking regulator (LYST), transcript variant1851 1, mRNA. MAGEA9 NM 005365 Homo sapiens MAGE family member A9(MAGEA9), mRNA. 1852 MAGEA9B NM 001080790 Homo sapiens MAGE familymember A9B (MAGEA9B), mRNA. 1853 MAGTI NM 032121 Homo sapiens magnesiumtransporter 1 (MAGT1), mRNA. 1854 MALT1 NM 006785 Homo sapiens MALT1paracaspase (MALT1), transcript variant 1, 1855 mRNA. MALT1 NM 173844Homo sapiens MALT1 paracaspase (MALT1), transcript variant 2, 1856 mRNA.MAP3K2 NM 006609 Homo sapiens mitogen-activated protein kinase kinasekinase 2 1857 (MAP3K2), mRNA. MAPK1 NM 002745 Homo sapiensmitogen-activated protein kinase 1 (MAPK1), transcript 1858 variant 1,mRNA MAPK1 NM 138957 Homo sapiens mitogen-activated protein kinase 1(MAPK1), transcript 1859 variant 2, mRNA. MAPK3 NM 001040056 Homosapiens mitogen-activated protein kinase 3 (MAPK3), transcript 1860variant 2, mRNA. MAPK3 NM 001109891 Homo sapiens mitogen-activatedprotein kinase 3 (MAPK3), transcript 1861 variant 3, mRNA. MAPK3 NM002746 Homo sapiens mitogen-activated protein kinase 3 (MAPK3),transcript 1862 variant 1, mRNA. MAVS NM 020746 Homo sapiensmitochondrial antiviral signaling protein (MAVS), 1863 transcriptvariant 1, mRNA. MAVS NM 001206491 Homo sapiens mitochondrial antiviralsignaling protein (MAVS), 1864 transcript variant 3, mRNA. MAVS NR037921 Homo sapiens mitochondrial antiviral signaling protein (MAVS),1865 transcript variant 2, non-coding RNA. MECP2 NM 004992 Homo sapiensmethyl-CpG binding protein 2 (MECP2), transcript 1866 variant 1, mRNA.MECP2 NM 001110792 Homo sapiens methyl-CpG binding protein 2 (MECP2),transcript 1867 variant 2, mRNA. MEX3C NM 016626 Homo sapiens mex-3 RNAbinding family member C (MEX3C), 1868 mRNA. MRE11A NM 005590 Homosapiens MRE11 homolog A, double strand break repair nuclease 1869(MRE11A), transcript variant 2, mRNA. MRE11A NM 005591 Homo sapiensMRE11 homolog A, double strand break repair nuclease 1870 (MRE11A),transcript variant 1, mRNA. MS4A1 NM 021950 Homo sapiens membranespanning 4-domains A1 (MS4A1), transcript 1871 variant 3, mRNA. MS4A1 NM152866 Homo sapiens membrane spanning 4-domains A1 (MS4A1), transcript1872 variant 1, mRNA. MSN NM 002444 Homo sapiens moesin (MSN), mRNA.1873 MYD88 NM 001172566 Homo sapiens myeloid differentiation primaryresponse 88 (MYD88), 1874 transcript variant 5, mRNA. MYD88 NM 001172567Homo sapiens myeloid differentiation primary response 88 (MYD88), 1875transcript variant 1, mRNA. MYD88 NM 001172568 Homo sapiens myeloiddifferentiation primary response 88 (MYD88), 1876 transcript variant 3,mRNA. MYD88 NM 001172569 Homo sapiens myeloid differentiation primaryresponse 88 (MYD88), 1877 transcript variant 4, mRNA. MYD88 NM 002468Homo sapiens myeloid differentiation primary response 88 (MYD88), 1878transcript variant 2, mRNA. NBN NM 002485 Homo sapiens nibrin (NBN),mRNA. 1879 NFIC NM 001245005 Homo sapiens nuclear factor I C (NFIC),transcript variant 4, mRNA. 1880 NFIC NM 205843 Homo sapiens nuclearfactor I C (NFIC), transcript variant 2, mRNA. 1881 NFIC NM 001245002Homo sapiens nuclear factor I C (NFIC), transcript variant 1, mRNA. 1882NFIC NM 001245004 Homo sapiens nuclear factor I C (NFIC), transcriptvariant 3, mRNA. 1883 NFIC NM 005597 Homo sapiens nuclear factor I C(NFIC), transcript variant 5, mRNA. 1884 NFKB1 NM 003998 Homo sapiensnuclear factor of kappa light polypeptide gene enhancer 1885 in B-cells1 (NFKB1), transcript variant 1, mRNA. NFKB1 NM 001165412 Homo sapiensnuclear factor of kappa light polypeptide gene enhancer 1886 in B-cells1 (NFKB1), transcript variant 2, mRNA. NFKB2 NM 001077494 Homo sapiensnuclear factor of kappa light polypeptide gene enhancer 1887 in B-cells2 (NFKB2), transcript variant 1, mRNA. NFKB2 NM 002502 Homo sapiensnuclear factor of kappa light polypeptide gene enhancer 1888 in B-cells2 (NFKB2), transcript variant 2, mRNA. NFKB2 NM 001261403 Homo sapiensnuclear factor of kappa light polypeptide gene enhancer 1889 in B-cells2 (NFKB2), transcript variant 4, mRNA. NFKBIA NM 020529 Homo sapiensNFKB inhibitor alpha (NFKBIA), mRNA. 1890 NHEJ1 NM 024782 Homo sapiensnon-homologous end joining factor 1 (NHEJ1), mRNA. 1891 NLRP3 NM 183395Homo sapiens NLR family, pyrin domain containing 3 (NLRP3), 1892transcript variant 2, mRNA. NLRP3 NM 004895 Homo sapiens NLR family,pyrin domain containing 3 (NLRP3), 1893 transcript variant 1, mRNA.NLRP3 NM 001127462 Homo sapiens NLR family, pyrin domain containing 3(NLRP3), 1894 transcript variant 5, mRNA. NLRP3 NM 001127461 Homosapiens NLR family, pyrin domain containing 3 (NLRP3), 1895 transcriptvariant 4, mRNA. NLRP3 NM 001079821 Homo sapiens NLR family, pyrindomain containing 3 (NLRP3), 1896 transcript variant 3, mRNA. NLRP3 NM001243133 Homo sapiens NLR family, pyrin domain containing 3 (NLRP3),1897 transcript variant 6, mRNA. NOD2 NM 022162 Homo sapiensnucleotide-binding oligomerization domain containing 2 1898 (NOD2),mRNA. ORAII NM 032790 Homo sapiens ORAI calcium release-activatedcalcium modulator 1 1899 (ORAI1), mRNA. OSTM1 NM 014028 Homo sapiensosteopetrosis associated transmembrane protein 1 1900 (OSTM1), mRNA.PGM3 NM 001199917 Homo sapiens phosphoglucomutase 3 (PGM3), transcriptvariant 1, 1901 mRNA. PGM3 NM 001199918 Homo sapiens phosphoglucomutase3 (PGM3), transcript variant 3, 1902 mRNA. PGM3 NM 015599 Homo sapiensphosphoglucomutase 3 (PGM3), transcript variant 2, 1903 mRNA, PGM3 NM001199919 Homo sapiens phosphoglucomutase 3 (PGM3), transcript variant4, 1904 mRNA. PIAS1 NM 016166 Homo sapiens protein inhibitor ofactivated STAT 1 (PIAS1), transcript 1905 variant 2, mRNA. PIK3R1 NM181523 Homo sapiens phosphoinositide-3-kinase regulatory subunit 1 1906(PIK3R1), transcript variant 1, mRNA. PIK3R1 NM 181524 Homo sapiensphosphoinositide-3-kinase regulatory subunit 1 1907 (PIK3R1), transcriptvariant 3, mRNA. PIK3R1 NM 181504 Homo sapiens phosphoinositide-3-kinaseregulatory subunit 1 1908 (PIK3R1), transcript variant 2, mRNA. PIK3R1NM 001242466 Homo sapiens phosphoinositide-3-kinase regulatory subunit 11909 (PIK3R1), transcript variant 4, mRNA. PLCG2 NM 002661 Homo sapiensphospholipase C gamma 2 (PLCG2), mRNA. 1910 PMS2 NM 000535 Homo sapiensPMS1 homolog 2, mismatch repair system component 1911 (PMS2), transcriptvariant 1, mRNA. PNP NM 000270 Homo sapiens purine nucleosidephosphorylase (PNP), mRNA. 1912 POLA1 NM 016937 Homo sapiens polymerase(DNA directed), alpha 1, catalytic subunit 1913 (POLA1), mRNA. POLE NM006231 Homo sapiens DNA polymerase epsilon, catalytic subunit (POLE),1914 mRNA. PRF1 NM 001083116 Homo sapiens perforin 1 (PRF1), transcriptvariant 2, mRNA. 1915 PRF1 NM 005041 Homo sapiens perforin 1 (PRF1),transcript variant 1, mRNA. 1916 PRKCD NM 006254 Homo sapiens proteinkinase C delta (PRKCD), transcript variant 1, 1917 mRNA. PRKCD NM 212539Homo sapiens protein kinase C delta (PRKCD), transcript variant 2, 1918mRNA. PRKDC NM 001081640 Homo sapiens protein kinase, DNA-activated,catalytic polypeptide 1919 (PRKDC), transcript variant 2, mRNA. PRKDC NM006904 Homo sapiens protein kinase, DNA-activated, catalytic polypeptide1920 (PRKDC), transcript variant 1, mRNA. PROC NM 000312 Homo sapiensprotein C, inactivator of coagulation factors Va and VIIIa 1921 (PROC),mRNA. PSMB8 NM 004159 Homo sapiens proteasome (prosome, macropain)subunit, beta type, 8 1922 (PSMB8), transcript variant 1, mRNA. PSMB8 NM148919 Homo sapiens proteasome (prosome, macropain) subunit, beta type,8 1923 (PSMB8), transcript variant 2, mRNA. PTEN NM 000314 Homo sapiensphosphatase and tensin homolog (PTEN), transcript 1924 variant 1, mRNA.PTPRC NM 001267798 Homo sapiens protein tyrosine phosphatase, receptortype C (PTPRC), 1925 transcript variant 5, mRNA. PTPRC NM 002838 Homosapiens protein tyrosine phosphatase, receptor type C (PTPRC), 1926transcript variant 1, mRNA. PTPRC NM 080921 Homo sapiens proteintyrosine phosphatase, receptor type C (PTPRC), 1927 transcript variant2, mRNA. PTPRC NR 052021 Homo sapiens protein tyrosine phosphatase,receptor type C (PTPRC), 1928 transcript variant 4, non-coding RNA. PURANM 005859 Homo sapiens purine rich element binding protein A (PURA),mRNA. 1929 RAB27A NM 183235 Homo sapiens RAB27A, member RAS oncogenefamily (RAB27A), 1930 transcript variant 3, mRNA. RAB27A NM 183236 Homosapiens RAB27A, member RAS oncogene family (RAB27A), 1931 transcriptvariant 4, mRNA. RAB27A NM 004580 Homo sapiens RAB27A, member RASoncogene family (RAB27A), 1932 transcript variant 1, mRNA. RAB27A NM183234 Homo sapiens RAB27A, member RAS oncogene family (RAB27A), 1933transcript variant 2, mRNA. RAB7A NM 004637 Homo sapiens RAB7A, memberRAS oncogene family (RAB7A), 1934 mRNA. RABGEF1 NM 014504 Homo sapiensRAB guanine nucleotide exchange factor (GEF) 1 1935 (RABGEF1),transcript variant 4, mRNA. RAC2 NM 002872 Homo sapiens ras-related C3botulinum toxin substrate 2 (rho family, 1936 small GTP binding proteinRac2) (RAC2), mRNA. RAD51 NM 001164270 Homo sapiens RAD51 recombinase(RAD51), transcript variant 3, 1937 mRNA. RAD51 NM 002875 Homo sapiensRAD51 recombinase (RAD51), transcript variant 1, 1938 mRNA. RAD51 NM133487 Homo sapiens RAD51 recombinase (RAD51), transcript variant 2,1939 mRNA. RAD51 NM 001164269 Homo sapiens RAD51 recombinase (RAD51),transcript variant 4, 1940 mRNA. RAG1 NM 000448 Homo sapiensrecombination activating gene 1 (RAG1), mRNA. 1941 RAG2 NM 000536 Homosapiens recombination activating gene 2 (RAG2), transcript 1942 variant1, mRNA. RAG2 NM 001243785 Homo sapiens recombination activating gene 2(RAG2), transcript 1943 variant 3, mRNA. RAG2 NM 001243786 Homo sapiensrecombination activating gene 2 (RAG2), transcript 1944 variant 4, mRNA.RBCK1 NM 006462 Homo sapiens RANBP2-type and C3HC4-type zinc fingercontaining 1 1945 (RBCK1), transcript variant 1, mRNA. RBCK1 NM 031229Homo sapiens RANBP2-type and C3HC4-type zinc finger containing 1 1946(RBCK1), transcript variant 2, mRNA. RFX5 NM 000449 Homo sapiensregulatory factor X5 (RFX5), transcript variant 1, 1947 mRNA. RFX5 NM001025603 Homo sapiens regulatory factor X5 (RFX5), transcript variant2, 1948 mRNA. RFXANK NM 003721 Homo sapiens regulatory factor Xassociated ankyrin containing protein 1949 (RFXANK), transcript variant1, mRNA. RFXANK NM 134440 Homo sapiens regulatory factor X associatedankyrin containing protein 1950 (RFXANK), transcript variant 2, mRNA.RFXAP NM 000538 Homo sapiens regulatory factor X associated protein(RFXAP), mRNA. 1951 RIPK1 NM 003804 Homo sapiens receptor(TNFRSF)-interacting serine-threonine kinase 1 1952 (RIPK1), mRNA. RIPK3NM 006871 Homo sapiens receptor-interacting serine-threonine kinase 3(RIPK3), 1953 mRNA. RMRP NR 003051 Homo sapiens RNA component ofmitochondrial RNA processing 1954 endoribonuclease (RMRP), RNase MRPRNA. RNASEH2A NM 006397 Homo sapiens ribonuclease H2, subunit A(RNASEH2A), mRNA. 1955 RNASEH2B NM 001142279 Homo sapiens ribonucleaseH2, subunit B (RNASEH2B), transcript 1956 variant 2, mRNA. RNASEH2B NM024570 Homo sapiens ribonuclease H2, subunit B (RNASEH2B), transcript1957 variant 1, mRNA. RNASEH2C NM 032193 Homo sapiens ribonuclease H2,subunit C (RNASEH2C), mRNA. 1958 RNASEL NM 021133 Homo sapiensribonuclease L (2′,5′-oligoisoadenylate synthetase- 1959 dependent)(RNASEL), mRNA. RNF168 NM 152617 Homo sapiens ring finger protein 168(RNF168), mRNA. 1960 RNF31 NM 017999 Homo sapiens ring finger protein 31(RNF31), mRNA. 1961 RNU4ATAC NR 023343 Homo sapiens RNA, U4atac smallnuclear (U12-dependent splicing) 1962 (RNU4ATAC), small nuclear RNA.RTEL1 NM 016434 Homo sapiens regulator of telomere elongation helicase 1(RTEL1), 1963 transcript variant 1, mRNA. RTEL1 NM 032957 Homo sapiensregulator of telomere elongation helicase 1 (RTEL1), 1964 transcriptvariant 2, mRNA. RTEL1- NR 037882 Homo sapiens RTEL1-TNFRSF6Breadthrough (NMD candidate) 1965 TNFRSF6B (RTEL1-TNFRSF6B), longnon-coding RNA. SALL2 NM 005407 Homo sapiens spalt like transcriptionfactor 2 (SALL2), transcript 1966 variant 1, mRNA. SAMHD1 NM 015474 Homosapiens SAM domain and HD domain 1 (SAMHD1), mRNA. 1967 SBDS NM 016038Homo sapiens Shwachman-Bodian-Diamond syndrome (SBDS), 1968 mRNA. SH2D1ANM 001114937 Homo sapiens SH2 domain containing 1A (SH2D1A), transcriptvariant 1969 2, mRNA. SH2D1A NM 002351 Homo sapiens SH2 domaincontaining 1A (SH2D1A), transcript variant 1970 1, mRNA. SHARPIN NM030974 Homo sapiens SHANK-associated RH domain interactor (SHARPIN),1971 transcript variant 1, mRNA. SHARPIN NR 038270 Homo sapiensSHANK-associated RH domain interactor (SHARPIN), 1972 transcript variant2, non-coding RNA. SKIV2L NM 006929 Homo sapiens superkiller viralicidicactivity 2-like (S. cerevisiae) 1973 (SKIV2L), mRNA. SLC37A4 NM001164277 Homo sapiens solute carrier family 37 (glucose-6-phosphate1974 transporter), member 4 (SLC37A4), transcript variant 1, mRNA.SLC37A4 NM 001164278 Homo sapiens solute carrier family 37(glucose-6-phosphate 1975 transporter), member 4 (SLC37A4), transcriptvariant 2, mRNA. SLC37A4 NM 001164279 Homo sapiens solute carrier family37 (glucose-6-phosphate 1976 transporter), member 4 (SLC37A4),transcript variant 3, mRNA. SLC37A4 NM 001467 Homo sapiens solutecarrier family 37 (glucose-6-phosphate 1977 transporter), member 4(SLC37A4), transcript variant 4, mRNA. SLC37A4 NM 001164280 Homo sapienssolute carrier family 37 (glucose-6-phosphate 1978 transporter), member4 (SLC37A4), transcript variant 5, mRNA. SLC46A1 NM 001242366 Homosapiens solute carrier family 46 member 1 (SLC46A1), transcript 1979variant 2, mRNA. SLC46A1 NM 080669 Homo sapiens solute carrier family 46member 1 (SLC46A1), transcript 1980 variant 1, mRNA. SLC8A1 NM 001112800Homo sapiens solute carrier family 8 member A1 (SLC8A1), transcript 1981variant B, mRNA. SLC8A1 NM 001112801 Homo sapiens solute carrier family8 member A1 (SLC8A1), transcript 1982 variant C, mRNA. SLC8A1 NM001112802 Homo sapiens solute carrier family 8 member A1 (SLC8A1),transcript 1983 variant D, mRNA. SLC8A1 NM 001252624 Homo sapiens solutecarrier family 8 member Al (SLC8A1), transcript 1984 variant E, mRNA.SLC8A1 NM 021097 Homo sapiens solute carrier family 8 member A1(SLC8A1), transcript 1985 variant A, mRNA. SMAD2 NM 001003652 Homosapiens SMAD family member 2 (SMAD2), transcript variant 2, 1986 mRNA.SMAD2 NM 001135937 Homo sapiens SMAD family member 2 (SMAD2), transcriptvariant 3, 1987 mRNA. SMAD2 NM 005901 Homo sapiens SMAD family member 2(SMAD2), transcript variant 1, 1988 mRNA. SMAD3 NM 005902 Homo sapiensSMAD family member 3 (SMAD3), transcript variant 1, 1989 mRNA. SMAD3 NM001145102 Homo sapiens SMAD family member 3 (SMAD3), transcript variant2, 1990 mRNA. SMAD3 NM 001145103 Homo sapiens SMAD family member 3(SMAD3), transcript variant 3, 1991 mRNA. SMAD3 NM 001145104 Homosapiens SMAD family member 3 (SMAD3), transcript variant 4, 1992 mRNA.SMAD4 NM 005359 Homo sapiens SMAD family member 4 (SMAD4), mRNA. 1993SNAP29 NM 004782 Homo sapiens synaptosomal-associated protein, 29 kDa(SNAP29), 1994 mRNA. SNAR- NR 004435 Homo sapiens smallILF3/NF90-associated RNA A1 (SNAR-A1), small 1995 A1 nuclear RNA. SNAR-NR 024229 Homo sapiens small ILF3/NF90-associated RNA A10 (SNAR-A10),1996 A10 small nuclear RNA. SNAR- NR 024225 Homo sapiens smallILF3/NF90-associated RNA A11 (SNAR-A11), 1997 A11 small nuclear RNA.SNAR- NR 004437 Homo sapiens small ILF3/NF90-associated RNA A12(SNAR-A12), 1998 A12 small nuclear RNA. SNAR- NR 024216 Homo sapienssmall ILF3/NF90-associated RNA A13 (SNAR-A13), 1999 A13 small nuclearRNA. SNAR- NR 024242 Homo sapiens small ILF3/NF90-associated RNA A14(SNAR-A14), 2000 A14 small nuclear RNA. SNAR- NR 004436 Homo sapienssmall ILF3/NF90-associated RNA A2 (SNAR-A2), small 2001 A2 nuclear RNA.SNAR- NR 024214 Homo sapiens small ILF3/NF90-associated RNA A3(SNAR-A3), small 2002 A3 nuclear RNA. SNAR- NR 024215 Homo sapiens smallILF3/NF90-associated RNA A4 (SNAR-A4), small 2003 A4 nuclear RNA. SNAR-NR 024223 Homo sapiens small ILF3/NF90-associated RNA A5 (SNAR-A5),small 2004 A5 nuclear RNA. SNAR- NR 024227 Homo sapiens smallILF3/NF90-associated RNA A6 (SNAR-A6), small 2005 A6 nuclear RNA. SNAR-NR 024224 Homo sapiens small ILF3/NF90-associated RNA A7 (SNAR-A7),small 2006 A7 nuclear RNA. SNAR- NR 024228 Homo sapiens smallILF3/NF90-associated RNA A8 (SNAR-A8), small 2007 A8 nuclear RNA. SNAR-NR 024226 Homo sapiens small ILF3/NF90-associated RNA A9 (SNAR-A9),small 2008 A9 nuclear RNA. SNAR- NR 024231 Homo sapiens smallILF3/NF90-associated RNA B1 (SNAR-B1), small 2009 B nuclear RNA. SNAR-NR 024230 Homo sapiens small ILF3/NF90-associated RNA B2 (SNAR-B2),small 2010 B2 nuclear RNA. SNAR- NR 024220 Homo sapiens smallILF3/NF90-associated RNA C1 (SNAR-C1), small 2011 C1 nuclear RNA. SNAR-NR 024217 Homo sapiens small ILF3/NF90-associated RNA C2 (SNAR-C2),small 2012 C2 nuclear RNA. SNAR- NR 024221 Homo sapiens smallILF3/NF90-associated RNA C3 (SNAR-C3), small 2013 C3 nuclear RNA. SNAR-NR 024218 Homo sapiens small ILF3/NF90-associated RNA C4 (SNAR-C4),small 2014 C4 nuclear RNA. SNAR- NR 024219 Homo sapiens smallILF3/NF90-associated RNA C5 (SNAR-C5), small 2015 C5 nuclear RNA. SNAR-DNR 024243 Homo sapiens small ILF3/NF90-associated RNA D (SNAR-D), small2016 nuclear RNA. SNAR-E NR 024258 Homo sapiens smallILF3/NF90-associated RNA E (SNAR-E), small 2017 nuclear RNA. SNAR-F NR004384 Homo sapiens small ILF3/NF90-associated RNA F (SNAR-F), small2018 nuclear RNA. SNAR- NR 004383 Homo sapiens smallILF3/NF90-associated RNA G1 (SNAR-G1), small 2019 G nuclear RNA. SNAR-NR 024244 Homo sapiens small ILF3/NF90-associated RNA G2 (SNAR-G2),small 2020 G2 nuclear RNA. SNAR-H NR 024342 Homo sapiens smallILF3/NF90-associated RNA H (SNAR-H), small 2021 nuclear RNA. SNAR-I NR024343 Homo sapiens small ILF3/NF90-associated RNA I (SNAR-I), small2022 nuclear RNA. SNCA NM 000345 Homo sapiens synuclein, alpha (non A4component of amyloid 2023 precursor) (SNCA), transcript variant 1, mRNA.SNCA NM 001146054 Homo sapiens synuclein, alpha (non A4 component ofamyloid 2024 precursor) (SNCA), transcript variant 2, mRNA. SNCA NM001146055 Homo sapiens synuclein, alpha (non A4 component of amyloid2025 precursor) (SNCA), transcript variant 3, mRNA. SNCA NM 007308 Homosapiens synuclein, alpha (non A4 component of amyloid 2026 precursor)(SNCA), transcript variant 4, mRNA. SNX10 NM 013322 Homo sapiens sortingnexin 10 (SNX10), transcript variant 2, mRNA. 2027 SNX10 NM 001199835Homo sapiens sorting nexin 10 (SNX10), transcript variant 1, mRNA. 2028SNX10 NM 001199837 Homo sapiens sorting nexin 10 (SNX10), transcriptvariant 3, mRNA. 2029 SNX10 NM 001199838 Homo sapiens sorting nexin 10(SNX10), transcript variant 4, mRNA. 2030 SNX10 NR 037670 Homo sapienssorting nexin 10 (SNX10), transcript variant 5, non- 2031 coding RNA.SP110 NM 004509 Homo sapiens SP110 nuclear body protein (SP110),transcript variant a, 2032 mRNA. SP110 NM 080424 Homo sapiens SP110nuclear body protein (SP110), transcript variant c, 2033 mRNA. SP110 NM001185015 Homo sapiens SP110 nuclear body protein (SP110), transcriptvariant d, 2034 mRNA. SP110 NM 004510 Homo sapiens SP110 nuclear bodyprotein (SP110), transcript variant b, 2035 mRNA. SP140 NM 001005176Homo sapiens SP140 nuclear body protein (SP140), transcript variant 2,2036 mRNA. SP140 NM 007237 Homo sapiens SP140 nuclear body protein(SP140), transcript variant 1, 2037 mRNA. SPINK5 NM 001127698 Homosapiens serine peptidase inhibitor, Kazal type 5 (SPINK5), 2038transcript variant 1, mRNA. SPINK5 NM 006846 Homo sapiens serinepeptidase inhibitor, Kazal type 5 (SPINK5), 2039 transcript variant 2,mRNA. SPINK5 NM 001127699 Homo sapiens serine peptidase inhibitor, Kazaltype 5 (SPINK5), 2040 transcript variant 3, mRNA. SQSTM1 NM 003900 Homosapiens sequestosome 1 (SQSTM1), transcript variant 1, mRNA. 2041 SQSTM1NM 001142298 Homo sapiens sequestosome 1 (SQSTM1), transcript variant 2,mRNA. 2042 SQSTM1 NM 001142299 Homo sapiens sequestosome 1 (SQSTM1),transcript variant 3, mRNA. 2043 SRSF1 NM 001078166 Homo sapiens serineand arginine rich splicing factor 1 (SRSF1), 2044 transcript variant 2,mRNA. SRSF1 NM 006924 Homo sapiens serine and arginine rich splicingfactor 1 (SRSF1), 2045 transcript variant 1, mRNA. SRSF1 NR 034041 Homosapiens serine and arginine rich splicing factor 1 (SRSF1), 2046transcript variant 3, non-coding RNA. STAT1 NM 007315 Homo sapienssignal transducer and activator of transcription 1 2047 (STAT1),transcript variant alpha, mRNA. STAT1 NM 139266 Homo sapiens signaltransducer and activator of transcription 1 2048 (STAT1), transcriptvariant beta, mRNA. STAT2 NM 005419 Homo sapiens signal transducer andactivator of transcription 2, 113 kDa 2049 (STAT2), transcript variant1, mRNA. STAT2 NM 198332 Homo sapiens signal transducer and activator oftranscription 2, 113 kDa 2050 (STAT2), transcript variant 2, mRNA. STAT3NM 003150 Homo sapiens signal transducer and activator of transcription3 2051 (STAT3), transcript variant 2, mRNA. STAT3 NM 139276 Homo sapienssignal transducer and activator of transcription 3 2052 (STAT3),transcript variant 1, mRNA. STAT3 NM 213662 Homo sapiens signaltransducer and activator of transcription 3 2053 (STAT3), transcriptvariant 3, mRNA. STAT5B NM 012448 Homo sapiens signal transducer andactivator of transcription 5B 2054 (STAT5B), mRNA. STIM1 NM 003156 Homosapiens stromal interaction molecule 1 (STIM1), transcript 2055 variant2, mRNA. STK4 NM 006282 Homo sapiens serine/threonine kinase 4 (STK4),mRNA 2056 STX11 NM 003764 Homo sapiens syntaxin 11 (STX11), mRNA. 2057STXBP2 NM 001127396 Homo sapiens syntaxin binding protein 2 (STXBP2),transcript variant 2058 2, mRNA. STXBP2 NM 001272034 Homo sapienssyntaxin binding protein 2 (STXBP2), transcript variant 2059 3, mRNA.STXBP2 NM 006949 Homo sapiens syntaxin binding protein 2 (STXBP2),transcript variant 2060 1, mRNA STXBP2 NR 073560 Homo sapiens syntaxinbinding protein 2 (STXBP2), transcript variant 2061 4, non-coding RNA.SYNCRIP NM 001159673 Homo sapiens synaptotagmin binding cytoplasmic RNAinteracting 2062 protein (SYNCRIP), transcript variant 2, mRNA. SYNCRIPNM 001159674 Homo sapiens synaptotagmin binding cytoplasmic RNAinteracting 2063 protein (SYNCRIP), transcript variant 3, mRNA. SYNCRIPNM 001159676 Homo sapiens synaptotagmin binding cytoplasmic RNAinteracting 2064 protein (SYNCRIP), transcript variant 5, mRNA. SYNCRIPNM 001159677 Homo sapiens synaptotagmin binding cytoplasmic RNAinteracting 2065 protein (SYNCRIP), transcript variant 6, mRNA. SYNCRIPNM 001253771 Homo sapiens synaptotagmin binding cytoplasmic RNAinteracting 2066 protein (SYNCRIP), transcript variant 7, mRNA. SYNCRIPNM 001159675 Homo sapiens synaptotagmin binding cytoplasmic RNAinteracting 2067 protein (SYNCRIP), transcript variant 4, mRNA. SYNCRIPNM 006372 Homo sapiens synaptotagmin binding cytoplasmic RNA interacting2068 protein (SYNCRIP), transcript variant 1, mRNA. T NM 001270484 Homosapiens T brachyury transcription factor (T), transcript variant 2, 2069mRNA. T NM 003181 Homo sapiens T brachyury transcription factor (T),transcript variant 1, 2070 mRNA. TAP1 NM 000593 Homo sapiens transporter1, ATP binding cassette subfamily B member 2071 (TAP1), transcriptvariant 1, mRNA. TAP2 NM 018833 Homo sapiens transporter 2, ATP bindingcassette subfamily B member 2072 (TAP2), transcript variant 2, mRNA.TAP2 NM 000544 Homo sapiens transporter 2, ATP binding cassettesubfamily B member 2073 (TAP2), transcript variant 1, B allele, mRNA.TAPBP NM 003190 Homo sapiens TAP binding protein (tapasin) (TAPBP),transcript 2074 variant 1, mRNA. TAPBP NM 172209 Homo sapiens TAPbinding protein (tapasin) (TAPBP), transcript 2075 variant 3, mRNA.TAPBP NM 172208 Homo sapiens TAP binding protein (tapasin) (TAPBP),transcript 2076 variant 2, mRNA. TAZ NM 000116 Homo sapiens tafazzin(TAZ), transcript variant 1, mRNA. 2077 TAZ NM 181312 Homo sapienstafazzin (TAZ), transcript variant 3, mRNA. 2078 TAZ NM 181311 Homosapiens tafazzin (TAZ), transcript variant 2, mRNA. 2079 TAZ NM 181313Homo sapiens tafazzin (TAZ), transcript variant 4, mRNA. 2080 TAZ NR024048 Homo sapiens tafazzin (TAZ), transcript variant 5, non-codingRNA. 2081 TBK1 NM 013254 Homo sapiens TANK binding kinase 1 (TBK1),mRNA. 2082 TBX1 NM 005992 Homo sapiens T-box 1 (TBX1), transcriptvariant B, mRNA. 2083 TBX1 NM 080646 Homo sapiens T-box 1 (TBX1),transcript variant A, mRNA. 2084 TBX1 NM 080647 Homo sapiens T-box 1(TBX1), transcript variant C, mRNA. 2085 TCIRG1 NM 006019 Homo sapiensT-cell immune regulator 1, ATPase H+ transporting V0 2086 subunit a3(TCIRG1), transcript variant 1, mRNA. TCIRG1 NM 006053 Homo sapiensT-cell immune regulator 1, ATPase H+ transporting V0 2087 subunit a3(TCIRG1), transcript variant 2, mRNA. TICAM1 NM 182919 Homo sapiens tolllike receptor adaptor molecule 1 (TICAM1), mRNA. 2088 TLR3 NM 003265Homo sapiens toll like receptor 3 (TLR3), mRNA. 2089 TLR4 NM 003266 Homosapiens toll like receptor 4 (TLR4), transcript variant 3, mRNA. 2090TLR4 NM 138554 Homo sapiens toll like receptor 4 (TLR4), transcriptvariant 1, mRNA. 2091 TLR4 NM 138557 Homo sapiens toll like receptor 4(TLR4), transcript variant 4, mRNA. 2092 TMEM173 NM 198282 Homo sapienstransmembrane protein 173 (TMEM173), mRNA. 2093 TNF NM 000594 Homosapiens tumor necrosis factor (TNF), mRNA. 2094 TNFAIP3 NM 001270507Homo sapiens TNF alpha induced protein 3 (TNFAIP3), transcript 2095variant 2, mRNA. TNFAIP3 NM 001270508 Homo sapiens TNF alpha inducedprotein 3 (TNFAIP3), transcript 2096 variant 1, mRNA. TNFAIP3 NM 006290Homo sapiens TNF alpha induced protein 3 (TNFAIP3), transcript 2097variant 3, mRNA. TNFRSF11A NM 003839 Homo sapiens tumor necrosis factorreceptor superfamily, member 11a, 2098 NFKB activator (TNFRSF11A),transcript variant 1, mRNA TNFRSF11A NM 001270949 Homo sapiens tumornecrosis factor receptor superfamily, member 11a, 2099 NFKB activator(TNFRSF11A), transcript variant 2, mRNA. TNFRSF11A NM 001270950 Homosapiens tumor necrosis factor receptor superfamily, member 11a, 2100NFKB activator (TNFRSF11A), transcript variant 3, mRNA. TNFRSF11A NM001270951 Homo sapiens tumor necrosis factor receptor superfamily,member 11a, 2101 NFKB activator (TNFRSF11A), transcript variant 4, mRNA.TNFRSF11B NM 002546 Homo sapiens tumor necrosis factor receptorsuperfamily, member 11b 2102 (TNFRSF11B), mRNA. TNFRSF13B NM 012452 Homosapiens TNF receptor superfamily member 13B (TNFRSF13B), 2103 mRNA.TNFRSF4 NM 003327 Homo sapiens TNF receptor superfamily member 4(TNFRSF4), 2104 mRNA. TNFRSF8 NM 001243 Homo sapiens TNF receptorsuperfamily member 8 (TNFRSF8), 2105 transcript variant 1, mRNA. TNFSF11NM 003701 Homo sapiens tumor necrosis factor (ligand) superfamily,member 11 2106 (TNFSF11), transcript variant 1, mRNA. TNFSF11 NM 033012Homo sapiens tumor necrosis factor (ligand) superfamily, member 11 2107(TNFSF11), transcript variant 2, mRNA. TNFSF12 NM 003809 Homo sapienstumor necrosis factor superfamily member 12 2108 (TNFSF12), transcriptvariant 1, mRNA. TNFSF12 NR 037146 Homo sapiens tumor necrosis factorsuperfamily member 12 2109 (TNFSF12), transcript variant 2, non-codingRNA. TP53 NM 000546 Homo sapiens tumor protein p53 (TP53), transcriptvariant 1, mRNA. 2110 TP53 NM 001126112 Homo sapiens tumor protein p53(TP53), transcript variant 2, mRNA. 2111 TP53 NM 001126113 Homo sapienstumor protein p53 (TP53), transcript variant 4, mRNA. 2112 TP53 NM001126114 Homo sapiens tumor protein p53 (TP53), transcript variant 3,mRNA. 2113 TP53 NM 001126115 Homo sapiens tumor protein p53 (TP53),transcript variant 5, mRNA. 2114 TP53 NM 001126116 Homo sapiens tumorprotein p53 (TP53), transcript variant 6, mRNA. 2115 TP53 NM 001126117Homo sapiens tumor protein p53 (TP53), transcript variant 7, mRNA. 2116TP53 NM 001126118 Homo sapiens tumor protein p53 (TP53), transcriptvariant 8, mRNA. 2117 TP53 NM 001276695 Homo sapiens tumor protein p53(TP53), transcript variant 4, mRNA. 2118 TP53 NM 001276696 Homo sapienstumor protein p53 (TP53), transcript variant 3, mRNA. 2119 TP53 NM001276697 Homo sapiens tumor protein p53 (TP53), transcript variant 5,mRNA. 2120 TP53 NM 001276698 Homo sapiens tumor protein p53 (TP53),transcript variant 6, mRNA. 2121 TP53 NM 001276699 Homo sapiens tumorprotein p53 (TP53), transcript variant 7, mRNA. 2122 TP53 NM 001276760Homo sapiens tumor protein p53 (TP53), transcript variant 1, mRNA. 2123TP53 NM 001276761 Homo sapiens tumor protein p53 (TP53), transcriptvariant 2, mRNA. 2124 TRAF3 NM 001199427 Homo sapiens TNF receptorassociated factor 3 (TRAF3), transcript 2125 variant 4, mRNA. TRAF3 NM003300 Homo sapiens TNF receptor associated factor 3 (TRAF3), transcript2126 variant 3, mRNA. TRAF3 NM 145725 Homo sapiens TNF receptorassociated factor 3 (TRAF3), transcript 2127 variant 1, mRNA. TRAF3 NM145726 Homo sapiens TNF receptor associated factor 3 (TRAF3), transcript2128 variant 2, mRNA. TRAF6 NM 004620 Homo sapiens TNFreceptor-associated factor 6, E3 ubiquitin protein 2129 ligase (TRAF6),transcript variant 2, mRNA. TRAF6 NM 145803 Homo sapiens TNFreceptor-associated factor 6, E3 ubiquitin protein 2130 ligase (TRAF6),transcript variant 1, mRNA. TREX1 NM 007248 Homo sapiens three primerepair exonuclease 1 (TREX1), transcript 2131 variant 5, mRNA. TREXI NM033629 Homo sapiens three prime repair exonuclease 1 (TREX1), transcript2132 variant 4, mRNA. TREX1 NM 016381 Homo sapiens three prime repairexonuclease 1 (TREX1), transcript 2133 variant 1, mRNA. TRNT1 NM 182916Homo sapiens tRNA nucleotidyl transferase 1 (TRNT1), transcript 2134variant 1, mRNA. TTC7A NM 020458 Homo sapiens tetratricopeptide repeatdomain 7A (TTC7A), transcript 2135 variant 2, mRNA. TYK2 NM 003331 Homosapiens tyrosine kinase 2 (TYK2), mRNA. 2136 UNC119 NM 005148 Homosapiens unc-119 lipid binding chaperone (UNC119), transcript 2137variant 1, mRNA. UNC119 NM 054035 Homo sapiens unc-119 lipid bindingchaperone (UNC119), transcript 2138 variant 2, mRNA. UNC13D NM 199242Homo sapiens unc-13 homolog D (UNC13D), mRNA. 2139 UNC93B1 NM 030930Homo sapiens unc-93 homolog B1 (C. elegans) (UNC93B1), mRNA. 2140 UNG NM080911 Homo sapiens uracil DNA glycosylase (UNG), transcript variant 2,2141 mRNA. UNG NM 003362 Homo sapiens uracil DNA glycosylase (UNG),transcript variant 1, 2142 mRNA. USP18 NM 017414 Homo sapiens ubiquitinspecific peptidase 18 (USP18), mRNA. 2143 USP20 NM 006676 Homo sapiensubiquitin specific peptidase 20 (USP20), transcript 2144 variant 1,mRNA. USP20 NM 001008563 Homo sapiens ubiquitin specific peptidase 20(USP20), transcript 2145 variant 2, mRNA. USP20 NM 001110303 Homosapiens ubiquitin specific peptidase 20 (USP20), transcript 2146 variant3, mRNA. VAPA NM 003574 Homo sapiens VAMP associated protein A (VAPA),transcript variant 2147 1, mRNA. VAPA NM 194434 Homo sapiens VAMPassociated protein A (VAPA), transcript variant 2148 2, mRNA. VCP NM007126 Homo sapiens valosin containing protein (VCP), mRNA. 2149 VDAC1NM 003374 Homo sapiens voltage dependent anion channel 1 (VDAC1),transcript 2150 variant 1, mRNA. VDAC1 NR 036624 Homo sapiens voltagedependent anion channel 1 (VDACI), transcript 2151 variant 3, non-codingRNA. VDAC1 NR 036625 Homo sapiens voltage dependent anion channel 1(VDAC1), transcript 2152 variant 2, non-coding RNA. VPS13B NM 017890Homo sapiens vacuolar protein sorting 13 homolog B (yeast) 2153(VPS13B), transcript variant 5, mRNA. VPS13B NM 181661 Homo sapiensvacuolar protein sorting 13 homolog B (yeast) 2154 (VPS13B), transcriptvariant 4, mRNA. VPS13B NM 015243 Homo sapiens vacuolar protein sorting13 homolog B (yeast) 2155 (VPS13B), transcript variant 3, mRNA. VPS13BNR 047582 Homo sapiens vacuolar protein sorting 13 homolog B (yeast)2156 (VPS13B), transcript variant 6, non-coding RNA. VPS13B NM 152564Homo sapiens vacuolar protein sorting 13 homolog B (yeast) 2157(VPS13B), transcript variant 1, mRNA. VPS45 NM 007259 Homo sapiensvacuolar protein sorting 45 homolog (VPS45), transcript 2158 variant 1,mRNA. WAS NM 000377 Homo sapiens Wiskott-Aldrich syndrome (WAS), mRNA.2159 WEE1 NM 003390 Homo sapiens WEE1 G2 checkpoint kinase (WEE1),transcript variant 2160 1, mRNA. WEE1 NM 001143976 Homo sapiens WEE1 G2checkpoint kinase (WEE1), transcript variant 2161 2, mRNA. WIPF1 NM001077269 Homo sapiens WAS/WASL interacting protein family member 1 2162(WIPF1), transcript variant 2, mRNA. WIPF1 NM 003387 Homo sapiensWAS/WASL interacting protein family member 1 2163 (WIPF1), transcriptvariant 1, mRNA. XIAP NM 001204401 Homo sapiens X-linked inhibitor ofapoptosis, E3 ubiquitin protein 2164 ligase (XIAP), transcript variant2, mRNA. XIAP NM 001167 Homo sapiens X-linked inhibitor of apoptosis, E3ubiquitin protein 2165 ligase (XIAP), transcript variant 1, mRNA. XIAPNR 037916 Homo sapiens X-linked inhibitor of apoptosis, E3 ubiquitinprotein 2166 ligase (XIAP), transcript variant 3, non-coding RNA. YBX1NM 004559 Homo sapiens Y-box binding protein 1 (YBX1), transcriptvariant 1, 2167 mRNA. YWHAZ NM 001135699 Homo sapiens tyrosine3-monooxygenase/tryptophan 5-monooxygenase 2168 activation protein zeta(YWHAZ), transcript variant 3, mRNA. YWHAZ NM 001135700 Homo sapienstyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2169 activationprotein zeta (YWHAZ), transcript variant 4, mRNA. YWHAZ NM 001135701Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2170activation protein zeta (YWHAZ), transcript variant 5, mRNA. YWHAZ NM001135702 Homo sapiens tyrosine 3-monooxygenase/tryptophan5-monooxygenase 2171 activation protein zeta (YWHAZ), transcript variant6, mRNA. YWHAZ NM 003406 Homo sapiens tyrosine3-monooxygenase/tryptophan 5-monooxygenase 2172 activation protein zeta(YWHAZ), transcript variant 1, mRNA. YWHAZ NM 145690 Homo sapienstyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2173 activationprotein zeta (YWHAZ), transcript variant 2, mRNA. ZAP70 NM 001079 Homosapiens zeta chain of T cell receptor associated protein kinase 70 2174(ZAP70), transcript variant 1, mRNA. ZAP70 NM 207519 Homo sapiens zetachain of T cell receptor associated protein kinase 70 2175 (ZAP70),transcript variant 2, mRNA. ZBTB24 NM 014797 Homo sapiens zinc fingerand BTB domain containing 24 (ZBTB24), 2176 transcript variant 1, mRNA.ZBTB24 NM 001164313 Homo sapiens zinc finger and BTB domain containing24 (ZBTB24), 2177 transcript variant 2, mRNA.

Table 12 lists all transcript variants for genes in Table 6 that werenot ‘discovered’ by PBio on the basis of aCGH (CNV identified genes).The SEQ ID NOs correspond to transcript variants (oftentimes more thanone per gene).

TABLE 13 Genes for which the total burden of heterozygous, damagingvariants was found to be statistically greater in PML cases versus ExACcontrols Ave Ave Ave FET Ave EXAC EXAC corr Ave GENE CASES CASES SAMPLESAve FET (419) OR Ethnicity Overlap PLCG2 17 1,806 31,277 1.43E−106.21E−08 10.27 EUR EUR + AFR RBCK1 6 187 29,324 4.27E−07 1.86E−04 24.60EUR EPG5 9 764 32,835 7.11E−07 3.09E−04 10.79 EUR IL17F 4 61 33,3461.67E−06 7.28E−04 54.57 EUR SHARPIN 8 646 32,162 2.58E−06 1.12E−03 10.84EUR PRF1 8 715 33,027 4.44E−06 1.93E−03 10.04 EUR JAGN1 5 163 27,7686.80E−06 2.96E−03 21.71 EUR TAP1 5 203 28,125 1.80E−05 7.82E−03 17.63EUR POLE 11 1,660 29,108 2.84E−05 1.23E−02 5.51 EUR EUR + AFR LRBA 111,876 32,136 3.47E−05 1.51E−02 5.38 EUR EHF 3 49 32,588 4.83E−052.10E−02 48.59 EUR IL12B 3 58 33,112 7.44E−05 3.23E−02 41.70 EUR ATL2 831 5,041 4.03E−11 1.75E−08 90.11 AFR NHEJ1 6 27 4,384 5.48E−09 2.39E−0664.56 AFR LYST 11 291 4,748 1.09E−08 4.76E−06 16.85 AFR HIVEP1 9 1504,432 7.41E−08 3.22E−05 23.83 AFR AP3B1 5 46 4,937 1.69E−06 7.36E−0433.23 AFR TNFRSF10A 7 149 4,626 3.28E−06 1.43E−03 15.03 AFR PIK3CD 7 1484,549 3.52E−06 1.53E−03 14.87 AFR PLCG2 8 256 4,410 1.47E−05 6.41E−039.99 AFR EUR + AFR PNP 3 11 5,189 2.00E−05 8.69E−03 78.45 AFR POLE 8 2974,752 2.48E−05 1.08E−02 9.23 AFR EUR + AFR MCEE 3 13 5,164 3.10E−051.35E−02 66.04 AFR DOCK2 6 173 5,023 6.39E−05 2.78E−02 11.21 AFR ALG12 443 4,252 6.73E−05 2.93E−02 23.03 AFR

Table 13 lists genes for which the total burden of heterozygous,damaging variants was found to be statistically greater in PML casesversus ExAC controls. Gene burden analysis was performed as describedbelow at minor allele frequency (MAF) cutoffs of 0.01, 0.02, 0.03, 0.04and 0.05. Not all genes survived statistical analysis at all MAFcutoffs. For each gene that survived at multiple MAF cutoffs, theaverages of the Fisher's Exact Test (FET), nominal and corrected, werecalculated, as were the other relevant metrics. Two genes overlappedbetween AFR and EUR analyses. FETs were corrected for multiple testingwith the number of genes used in this study (419). Only genes for whichFET corr was <0.05 and in which variants affected >10% of cases withinthe given ethnicity (>2 for AFR, >4 for FUR) were considered forinclusion.

TABLE 14 Top tier of variants found to be significant on the basis ofvariant burden analysis PML PML PML PML PML PML PML PML PML Variant GenoEUR AFR LAT ExAC ExAC ExAC EUR EUR AFR AFR ALL ALL Gene (hg19) type 4421 5 EUR AFR LAT OR FET OR FET OR FET PLCG2 chr16: het 2 5 0 512/ 88/116/ 2.95 0.154755 16.40 0.0000 6.49 0.0002 81942175, 32281 4707 5548A > G IFIH1 chr2: het 6 1 0 611/ 23/ 119/ 8.41 0.000156 11.22 0.09276.38 0.0002 163136505, 33155 5182 5671 C > G TCIRG1 chr11: het 0 4 0103/ 200/ 60/ NA NA 5.85 0.0082 7.31 0.0028 67818269, 33193 5170 5770G > A IGLL1 chr22: het 4 3 1 751/ 603/ 236/ 4.34 0.017218 1.27 0.72863.47 0.0036 23917192, 33348 5183 5782 G > T MAVS chr20: hom 4 4 0 800/684/ 152/ 3.92 0.023868 1.48 0.5191 3.47 0.0036 3846397, 32122 4982 5691C > T SHARPIN chr8: het 8 4 0 2916/ 59/ 171/ 2.31 0.053526 19.17 0.00012.68 0.0040 145154222, 33177 4865 5780 G > A CHD7 chr8: het 5 0 0 1103/39/4840 2593/ 3.72 0.015268 NA NA 2.64 0.0485 61654298, 33106 5725 T > ACX3CR1 chr3: hom 1 4 0 4723/ 193/ 1357/ 1.87 0.088087 5.10 0.0128 1.510.1806 39323163, 31219 4376 5491 A > C LRBA chr4: hom 3 3 0 2260/ 20/54/ 1.01 1.000000 43.13 0.0001 1.69 0.2736 151199080, 33328 5195 5785G > A HIVEP3 chr1: het 5 3 1 3383/ 123/ 902/ 1.10 0.803620 6.69 0.01431.30 0.4283 42047208, 32494 5061 5756 C > G IFIH1 chr2: hom 20 3 112107/ 184/ 1076/ 1.46 0.212471 4.54 0.0374 1.21 0.4372 163124051, 333565199 5776 C > T RNASEL chr1: hom 7 2 0 4543/ 78/ 167/ 1.20 0.658473 6.910.0403 1.22 0.5616 182554557, 33356 5202 5785 C > T

Table 14 lists the top tier of variants that were found to besignificant on the basis of variant burden analysis, as described below.For each variant (genome coordinates are based on UCSC hg19), detailedinformation is presented of the numbers of EUR and AFR cases that carrythe variant, along with the ethnic-specific and aggregate statisticalmetrics.

TABLE 15 Second tier of variants found on the basis of variant burdenanalysis PML PML PML PML PML PML PML PML PML Variant Geno EUR AFR LATExAC ExAC ExAC EUR EUR AFR AFR ALL ALL Gene (hg19) type 44 21 5 EUR AFRLAT OR FET OR FET OR FET SHARPIN chr8: het 3 0 0 2/30,670 0/4,4710/5,302 1122.00 0.000000 NA NA 905.40 0.0000 145154824, A > C RTEL1chr20: het 0 2 0 1/32,552 0/4,838 0/5,737 NA NA 1240.64 0.0000 1268.410.0000 62305450, C > T IGLL1 chr22: het 2 0 1 19/ 74/5,184 9/5,783 83.530.000351 NA NA 19.41 0.0006 23915745, 33,348 G > A PGM3 chr6: het 0 2 00/ 6/5,167 3/5,748 NA NA 20.81 0.0055 44.58 0.0011 83884161, 33,0269 C >G ATM chr11: het 3 0 0 170/ 3/5,099 7/5,713 14.00 0.001636 NA NA 10.780.0032 108202772, 32,707 G > T TME173 chr5: het 2 2 0 108/ 204/4,8427058/5,7 14.21 0.009863 2.39 0.2226 6.97 0.0033 138856923, 32,327 C > TCLCN7 chr16: het 0 2 0 1/32,898 66/5,119 0/5,732 NA NA 8.06 0.0308 19.180.0055 1510535, C > T MAVS chr20: hom 4 2 0 803/ 167/5,171 46/5,779 4.040.021706 3.15 0.1480 3.98 0.0056 3843027, 33,206 C > A ORAI1 chr12: het4 0 0 371/ 5/3,555 16/5,3 7.64 0.002562 NA NA 5.76 0.0064 122064788,28,708 G > GT RBFOX1 chr16: het 0 2 0 1/33,367 69/4,902 4/5,782 NA NA7.37 0.0361 17.48 0.0066 7714909, C > T MALT1 chr18: het 4 0 0 466/9/5,179 40/5,760 7.03 0.003411 NA NA 5.14 0.0093 56401523, 33,239 C > TGFI1 chr1: het 2 1 0 206/ 6/4,156 39/5,114 6.68 0.039391 34.58 0.03476.80 0.0113 92946625, 29,111 G > C DOCK2 chr5: het 0 2 0 48/ 43/5,20127/5,786 NA NA 12.63 0.0137 11.02 0.0155 169081453, 33,350 G > C ATMchr11: het 2 0 0 93/ 12/5,15 5628/5,7 16.98 0.00704 NA NA 10.53 0.0169108117787, 33,256 C > T SNAP29 chr22: het 3 0 0 283/ 21/5,149 32/5,7408.44 0.006584 NA NA 5.79 0.0171 21235389, 32,917 A > G TICAM1 chr19: het0 2 0 32/ 71/4,814 19/5,687 NA NA 7.03 0.0392 10.08 0.0183 4817657,31,437 C > T GTPBP4 chr10: hom 3 0 0 334/ 20/5,202 21/5,786 7.240.009925 NA NA 5.25 0.0220 1060218, 33,367 G > A BACH1 chr21: het 2 0 0134/ 4/5,103 6/5,778 11.72 0.014110 NA NA 8.96 0.0227 30698953, 33,122T > G DOCK8 chr9: het 2 0 0 149/ 2/5,161 5/5,762 10.59 0.017020 NA NA8.31 0.0261 304628, 33,298 G > A STXBP2 chr19: het 2 0 0 161/ 4/4,62611/5,686 9.45 0.021028 NA NA 7.06 0.0350 7712287, 32,104 G > C FASchr10: het 2 0 0 175/ 3/5,182 10/5,731 9.01 0.022902 NA NA 6.89 0.036590771767, 33,304 G > A GOLGB1 chr3: het 3 2 0 1,111/ 26/5,179 84/5,7792.12 0.180743 20.86 0.0055 2.71 0.0443 121415370, 33,349 T > C FUKchr16: het 4 0 0 741/ 23/4,899 73/5,787 4.40 0.016488 NA NA 3.13 0.044970503095, 33,341 A > G IL10 chr1: het 2 0 0 206/ 2/5,198 6/5,787 7.660.030787 NA NA 6.06 0.0458 206945738, 33,343 C > T ITK chr5: het 2 0 0206/ 5/5,203 5/5,789 7.66 0.030770 NA NA 6.01 0.0466 156593120, 33,353C > T STIM2 chr4: het 2 0 0 219/ 5/5,202 9/5,789 7.21 0.034346 NA NA5.57 0.0532 27019452, 33,369 C > T ASH1L chr1: het 2 0 0 218/ 2/5,20317/5,789 7.24 0.034067 NA NA 5.48 0.0548 155317682, 33,367 C > T TBC1D16chr17: het 3 0 0 496/ 15/4,845 21/5,707 4.63 0.031269 NA NA 3.53 0.058477926526, 31,905 C > T LYST chr1: het 3 0 0 517/ 10/5,156 35/5,756 4.630.031299 NA NA 3.47 0.0606 235840495, 33,239 G > T SALL2 chr14: het 3 00 519/ 14/4,520 17/5,718 4.40 0.035528 NA NA 3.37 0.0650 21993359,31,729 G > A CHD7 chr8: het 3 0 0 517/ 14/4,872 41/5,765 4.58 0.032169NA NA 3.36 0.0654 61757805, 32,880 C > T BLM chr15: het 2 0 0 266/10/5,061 17/5,756 5.91 0.048875 NA NA 4.40 0.0799 91306241, 33,277 G > ANOD2 chr16: het 0 2 0 285/ 21/5,203 2/5,789 NA NA 25.97 0.0037 4.210.0860 50741791, 33,369 C > T IGLL1 chr22: het 2 0 0 265/ 21/5,18326/5,787 5.94 0.048403 NA NA 4.15 0.0881 23915583, 33,334 T > C TTC7Achr2: het 3 0 0 589/ 13/5,173 61/5,759 4.05 0.043427 NA NA 2.94 0.089147205921, 33,202 C > T KITLG chr12: het 4 0 0 1,023/ 31/5,158 40/5,7603.15 0.046242 NA NA 2.38 0.0964 88900891, 33,226 C > A ATR chr3: het 4 00 1,037/ 14/5,130 69/5,785 3.12 0.047671 NA NA 2.33 0.1021 142281353,33,343 C > G ATM chr11: het 0 2 0 217/ 66/4,955 40/5,425 NA NA 7.800.0327 3.64 0.1093 108123551, 29,921 C > T CR2 chr1: het 0 2 0 391/19/5,203 8/5,754 NA NA 28.72 0.0031 3.09 0.1422 207641950, 33,363 C > THIVEP2 chr6: het 3 2 0 1,718/ 50/4,901 209/5,788 1.35 0.494339 10.210.0202 1.64 0.2458 143092151, 33,370 T > C ITSN2 chr2: hom 3 2 0 2,019/17/5,186 55/5,784 1.14 0.748301 32.01 0.0025 1.55 0.3862 24431184,33,339 C > T ITSN2 chr2: hom 3 2 0 2,026/ 17/4,958 56/5,672 1.100.753875 30.59 0.0028 1.50 0.3937 24432937, 32,472 C > T DOCK8 chr9: het3 2 0 2,114/ 79/5,180 161/5,768 1.08 0.757661 6.80 0.0415 1.37 0.4238312134, 33,251 G > A VPS13B chr8: het 0 2 0 811/ 19/5,192 100/5,778 NANA 28.66 0.0031 1.37 0.6600 100205255, 33,345 G > A NRIP1 chr21: het 0 20 901/ 19/5,203 64/5,780 NA NA 28.72 0.0031 1.30 0.6698 16339852, 33,355T > C

Table 15 lists the second tier of variants that were found on the basisof variant burden analysis, as described below. For each variant (genomecoordinates are UCSC hg19), detailed information is presented of thenumbers of EUR and AFR cases that carry the variant, along with theethnic-specific and aggregate statistical metrics.

TABLE 16 Potential testing scenario, based on top variant burden hitsProportion Patient information Cases of Cohort Test Primary Gene/Variantsolved (n = 70) Method disease Ethnicity Gender All 4 SNVs 28 40%genotyping M, H, O A, E both SHARPIN, IFIH1, PLCG2 24 34% genotyping M,H, O A, E both SNVs IFIH1, PLCG2 SNVs 13 19% genotyping M, H, O A, Eboth SHARPIN SNV 13 19% genotyping M, H A, E both IFIH1 SNV 7 10%genotyping M, H, O A, E both PLCG2 SNV 7 10% genotyping M, H A, E bothCHD7 SNV 5  7% genotyping M, H, O E both

Table 16 lists a potential testing scenario, based on top variant burdenhits (reported in Table 14). The analysis is for illustrative purposesonly, it being acknowledged that greater diagnostic yields can beobtained by assaying for a larger number of variants, including thoselisted in Table 15. Examples are given for diagnostic yield usingsingleton variants, as well as a variety of combinations, including theuse of the top 4 variants. For this set of variants, the test method isdescribed as genotyping, as opposed to whole gene sequencing (e.g.,determination of the status at each of the bases, which yields a binaryoutput, as opposed to identification of variants elsewhere in therelevant genes).

TABLE 17 Potential testing scenario using genes identified as having agreater burden of damaging, heterozygous variants in the PML cohortEthnic- Ave Specific Overall Yield Test Gene Cases Ethnicity Yield (%)(Eur + Afr) (%) Method PLCG2 17/44 EUR 38 38 Gene sequencing PLCG2  8/21AFR 38 Gene sequencing POLE  8/21 AFR 38 Gene sequencing POLE 11/44 EUR25 29 Gene sequencing LRBA 11/44 EUR 25 Gene sequencing EPG5  9/44 EUR20 Gene sequencing SHARPIN  8/44 EUR 18 Gene sequencing

Table 17 lists a potential testing scenario using genes identified ashaving a greater burden of damaging, heterozygous variants in the PMLcohort (see Table 13). The nature of the testing method is ‘genesequencing’ since the variants are not known in advance—any and allpotentially damaging variants need to be considered in such an assay.

TABLE 18 Summary of genes that survive case-level, gene burden and/ orvariant burden analyses Case Variant Gene Gene Level Burden Burden PLCG2Yes Yes Yes CHD7 Yes Yes IFIH1 Yes Yes AP3B1 Yes Yes EPG5 Yes Yes PIK3CDYes Yes LRBA Yes Yes SHARPIN Yes Yes

Table 18 represents a summary of genes that survive case-level (2 ormore examples in Tables 7, 8), gene burden and/or variant burdenanalyses (based on Tables 13 and 14). Of note is that PLCG2 satisfiesall 3 criteria (2 or more examples, in Table 8, presence in Tables 13,14). This summary demonstrates that many genes have been identified assignificant on the basis of independent analysis methods.

Example 11—Figures Referenced in this Study

FIGS. 1-12 represent example CNV data from the PML gene discovery study(71 PML cases, see Table 7 for patient information) using array CGH(methods described herein). In each figure/drawing: 1) genomecoordinates are listed at the top (hg18 assembly, chromosome number andposition depicted); 2) data track 1 (labeled ‘Genes’) depicts thelocation of the RefSeq genes (exons are dark gray portions of the bars,introns are light gray portions of the bars); 3) data track 2 (labeled‘Normal Cohort’) depicts the size and location of CNVs found in the NVEcohort (PBio's proprietary control database consisting of CNV findingsin apparently healthy—e.g. normal—subjects, see methods herein) with they-axis corresponding to the number of NVE subjects that have the CNV;and 4) remaining data tracks are CNV data found in individual PMLpatients wherein the y-axis corresponds to the log 2 ratio (see methodsherein), points represent individual probes on the microarray, and linesegments are shifted positive (copy number gain) or negative (copynumber loss) based on the output of DNAcopy, the CNV calling algorithm.Typical log 2 ratios for gains and losses on the Agilent 1M microarray(see methods herein) and our experimental protocols are: 0.6 forduplications, 1.0 for triplications (or homozygous duplications), −1.0for heterozygous deletions, and <−2 (often −4.0 to −6.0) for homozygousdeletions. Relevant genes are labeled in the ‘Genes’ data track.

FIG. 1 represents an example of a gene impacted by germline and acquiredCNVs. Germline CNVs that impact the PRKCB gene include patient PML50with a 4.8 Kb intronic heterozygous loss (also found in 7 Normalsubjects) and patient PML11 with a 7.3 Kb intronic gain (also found in 1Normal subject). Acquired CNVs were found in 6 PML patients, a series ofgains at −23.9 Mb with varying log 2 ratios, suggestive of a mixed cellpopulation (array CGH experiments were performed on blood-derivedgenomic DNA).

FIG. 2 represents an example of potentially PML-relevant genes(TNFRSF13C and CENPM) impacted by acquired CNVs. Acquired CNVs werefound in 9 PML patients, a series of gains at ˜40.6 Mb with varying log2 ratios, suggestive of a mixed cell population (array CGH experimentswere performed on blood-derived genomic DNA). All 9 PML patients (seeTable 7 for patient information) had a primary diagnosis of HIV and weremixed gender (3 females and 6 males) and ethnicity (4 African ancestryand 5 European ancestry).

FIG. 3 represents an example of a gene impacted by CNVs. A 7.2 Kbintronic heterozygous loss (not found in Normal subjects, but anadjacent loss is found in 8 Normal subjects) that impacts the PKHD1gene, was detected in patient PML26. CNVs were found in 3 PML patients,a series of gains at ˜51.9 Mb with varying log 2 ratios, suggestive of amixed cell population (array CGH experiments were performed onblood-derived genomic DNA).

FIG. 4 represents an example of a gene impacted by a CNV loss. The 14.7Kb intronic deletion impacts the BMPR2 gene. Heterozygous deletions weredetected in patients PML58 and MVGS811-13a (also found in 2 Normalsubjects), and a homozygous deletion was detected in patient PML29 (nonefound in Normal subjects). All three PML patients are males and theirprimary disease is HIV (see Table 7).

FIG. 5 represents an example of a gene impacted by a CNV gain. The 10.2Kb exonic gain disrupts the COMMD6 gene. Two PML patients, PML29 andMVGS811-13a, have a homozygous duplication (log 2 ratio comparable totriplications) based on the observation that 1000 genomes subjects arereported to have this gain (see hg19 assembly DGV variant esv3632749,which reports 148 of 2504 subjects as having this gain; no Normals werefound in PBio's NVE db). Both PML patients are males and their primarydisease is HIV (see Table 7).

FIG. 6 represents an example of a gene impacted by a CNV gain. The 27.4Kb exonic gain disrupts the KCTD7 gene and the right breakpoint is 16-90Kb upstream of RABGEF1 transcript variants (RefSeq: NM 001287060, NR104676, NM 014504, NM 001287062, NM 001287061). Patient PML29 has ahomozygous duplication (log 2 ratio comparable to triplications) basedon the observation that 1000 genomes subjects are reported to have thisgain (see hg19 assembly DGV variant esv3613515, which reports 28 of 2504subjects as having this gain; no Normals were found in PBio's NVE db).Patient PML63 has a duplication. Both PML patients are males of Africanancestry and their primary disease is HIV (see Table 7).

FIG. 7 represents an example of a gene impacted by a CNV gain. The 344Kb exonic gain disrupts the FPR2 and ZNF616 genes (via left and rightbreakpoints) and additional genes fully encompassed by this CNV are:FPR3, ZNF350, ZNF350-AS1, ZNF432, ZNF577, ZNF613, ZNF614, ZNF615,ZNF649, ZNF649-AS1, ZNF841. Patient PMLO3 has a homozygous duplication(log 2 ratio comparable to triplications) based on the observation that3 Normal subjects (PBio's NVE db) are found to have a duplication ofthis region, along with patient PML10. Both PML patients are females ofEuropean ancestry and their primary diseases are HIV and MS (see Table7).

FIG. 8 represents an example of a gene impacted by a CNV loss. The 1.1Kb exonic deletion impacts the PIK3CD and PIK3CD-AS1 (previous genesymbol was C1orf200) genes. A homozygous deletion was detected inpatient MVGS811-13a and this loss (heterozygous or homozygous) was notfound in Normal subjects or the DGV public CNV database. The PML patientis a male and his primary disease is HIV (see Table 7). He is presumedto be of EUR ancestry (ethnicities were not available for MVGS samples).

FIG. 9 represents an example of a gene impacted by an intergenic CNVgain. The 16.7 Kb intergenic gain has a left breakpoint that is 105 Kbupstream of the CD180 gene (RefSeq transcript variant NM 005582).Patient MVGS995-4a has a homozygous duplication (log 2 ratio comparableto triplications) based on the observation that 1000 genomes subjectsare reported to have this gain (see hg19 assembly DGV variantesv3605336, which reports 2 of 2504 subjects as having this gain; noNormals were found in PBio's NVE db). The PML patient is a male ofEuropean ancestry and his primary disease is MS (see Table 7).

FIG. 10 represents an example of a gene impacted by an intergenic CNVloss. The 7.7 Kb intergenic homozygous deletion has a left breakpointthat is 3-4 Kb upstream of VDAC1 transcript variants (RefSeq: NM 003374,NR 036625, NR 036624). This loss (heterozygous or homozygous) was notfound in Normal subjects or the DGV public CNV database. Patient PML30is a male of European ancestry and his primary disease is HIV (see Table7).

FIG. 11 represents an example of a gene impacted by an intergenic CNVloss. The 6.8 Kb intergenic homozygous deletion has a left breakpointthat is 4 Kb downstream of EGR1 transcript variant (RefSeq: NM 001964)and 26 Kb downstream of ETF1 transcript variants (RefSeq: NM 001256302,NM 004730, NM 001282185, NM 001291975, NM 001291974). This loss wasfound to be homozygous in 1 Normal subject and the loss was alsoreported in the DGV public CNV database (see hg19 assembly DGV variantesv3606925, which reports 33 of 2504 subjects as having this loss,homozygous vs. heterozygous subjects are unknown). Patient PML69 is amale of European ancestry and his primary disease (condition) is kidneytransplant (see Table 7, reported as ‘Other’). Patient PML69 was treatedwith CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cellanergy inducer). The CD28 pathway includes links to the patient'sgenetic finding (e.g., homozygous deletion adjacent to the EGR1 gene)and several other genes that may be related to immunodeficiency (e.g.,CD40LG, ITK, LCK, LRBA, PIK3CD, PIK3R1, PLCG2, WAS, and ZAP70) (DekeyserM et al. Open Forum Infect Diseases, 2016, Refractory T-Cell Anergy andRapidly Fatal Progressive Multifocal Leukoencephalopathy followingProlonged CTLA4 Therapy).

FIG. 12 represents an example of a gene impacted by an intergenic CNVloss. The 5.6 Kb intergenic homozygous deletion has a left breakpointthat is 20 Kb upstream of ITSN2 transcript variants (RefSeq: NM 019595,NM 006277, NM 147152). Heterozygous losses were found in 50 Normalsubjects and the loss was also reported in the DGV public CNV database(see hg19 assembly DGV variant esv3590068, which reports 222 of 2504subjects as having this loss, homozygous vs. heterozygous subjects areunknown). Patient PML65 is a male of African ancestry and his primarydisease is HIV (see Table 7).

FIG. 13 represents an example of known and/or predicted proteininteractions using the String database (string-db.org; see Szklarczyk etal., (2015) and references therein). A non-redundant list of all genesreported in Table 7 (43 genes, which included those whose expression wasinferred to be impacted by a nearby intergenic CNV) as bestsolutions/explanations for 61 of 71 PML cases (11 PML cases are reportedas ‘unsolved’, including 1 case for which only CGH data was obtained)was assessed using the String db. The ‘minimum required interactionscore’ was set to ‘high confidence (0.7)’ and no additional‘interactors’ were added. Of the 43 input genes, 21 were found to havehigh confidence interactions, as shown in the figure, along withannotation of the number of PML cases that had each of these genes as asolution/explanation (e.g., 3 PML cases in Table 7 were found to have aPLCG2 solution).

Example 12—Gene Burden Analysis

Gene burden analysis was performed as follows. Using a variety ofin-house scripts, and data downloaded from ExAC(exac.broadinstitute.org), a count was performed for all variantsoccurring in each of the 419 genes listed in Table 6. Each variant wasclassified according to whether it was deemed damaging (on the basis ofat least one of the prediction algorithms SIFT, PolyPhen2 orMutationTaster) or non-damaging, heterozygous or homozygous. This wasperformed in parallel for PML variants and those found in ExAC. ExACdata for which quality/coverage was <80% of expected was not used andgene burden analysis could not therefore be performed.

An ethnic-specific (EUR or AFR only, there were too few LAT cases forthis type of analysis) comparison was then performed for each of 4categories:

-   -   Homozygous damaging    -   Homozygous non-damaging    -   Heterozygous damaging    -   Heterozygous non-damaging

For all 4 categories, variants with minor allele frequency (MAF) cutoffsof 0.01, 0.02. 0.03. 0.04, 0.05 and 0.1 were considered.

For each comparison, odds ratios (OR) and Fisher's exact test (FET) werecalculated for the comparison of numbers of PML cases with at least onevariant of the type under consideration and those in ExAC. Correctionfor multiple testing was performed by multiplying the FET by the numberof genes being considered (419). Only genes for whom the FET correctedwas <0.05 were included in Table 13, which contains data on the averagevalues for a given gene at all MAFs that passed FET correction. Inpractice, only the category of heterozygous damaging yielded significantgenes.

Example 13—Variant Burden Analysis

For each variant identified in at least one PML case, a count wasperformed in order to obtain the frequency of the same variant in thecohort as a whole. This aggregate data was compared to counts for thesame variant as reported in ExAC. ExAC data was filtered forquality/coverage and variant burden analysis was not performed if ExACcoverage was <80% expected.

Variant burden analysis was performed separately for EUR (n=44 cases)and AFR (n=21 cases) cohorts (LAT cohort was too small) and the OR andFET values calculated. From this analysis, only variants with OR >1(e.g., potentially indicative of increased risk for PML) for bothethnicities (AFR and EUR) and for which the ExAC frequency of thevariant was <5% were considered. Furthermore, only those variants forwhich the frequency in the ethnic-specific cohort was >10% (5 or moreEUR cases, 3 or more AFR cases) were considered top-tier (Table 14),although other variants have been tabulated in Table 15.

Example 14—Exemplary PML Risk Prediction Tests

Table 16 provides exemplary markers for creating a low-cost, simple(genotype specific SNVs) PML risk prediction test. Other embodimentscould be similarly devised from other SNVs reported in Tables 14 and 15.Different combinations of SNVs from Tables 14, 15 could be utilized intests of varying complexity, to develop a test that would yield higherdiagnostic yields than the top example listed in Table 16 (e.g., 40%).

Table 17 provides exemplary genes that could be included in a gene panelsequencing test for PML risk prediction. Other embodiments could besimilarly devised from genes reported in Table 13, or from other tablesdisclosed herein.

Table 9 contains ‘example’ variants that may be considered as ‘AD’causes of immunodeficiency (e.g., presence of just 1 of the 2 reportedhet SNVs in a given patient may be causing immunodeficiency), which mayincrease the risk for PML. For example, this may be a more likelyscenario for het SNVs that are ‘novel’ in the ExAC db (e.g., not foundin the general population), and even more likely if such novel SNVs arefound in >=2 PML cases (irrespective of the invoked disease model).Examples of this include the following 3 genes:

-   -   AK2, 2 cases (Table 9), chr1:33476435, C>A, novel in ExAC PML20        and PML33, AFR and EUR, both HIV    -   EPG5, 2 cases (Table 9), chr18: 43445601, T>G, novel in ExAC        PML25 and PML27, both EUR, both HIV    -   TNFRSF11A, 9 cases (Table 7), chr18: 60052034, A>C, novel in        ExAC, see Table 7 for case IDs, 2 AFR and 7 EUR, all HIV

It can be appreciated by those skilled in the art that immunodeficiencygenes presently known to cause AR disease may potentially cause ADdisease. Numerous examples have been reported in the literature,including several of the genes listed in Table 6 (e.g., Disease model isindicated as AD AR for 32 genes, such as ADAR and TICAM1).

Example 15—Exemplary 96-Gene Panel PML Risk Prediction Tests

Table 19 contains an exemplary 96-gene panel based on genes that werefound to have at least one PML case count from Tables 7 and 8. The“Genes” and “Case level solutions” columns showed genes and total numberof PML cases (with at least one ‘case level’ solution) reported inTables 7 and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS,PLCG2, SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’values <0.05 (column O) were also included in Table 19. Among these 7genes, 3 genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALLFET’ values <0.05 (column O) from Table 15.

TABLE 19 exemplary 96-gene panel Genes Case level solutions AP3B1 5APOL1 1 ASH1L 1 ATM 1 ATR 3 BLM 1 CARD11 3 CDKN1B 1 CHD7 4 CLCN7 1DCLRE1C 3 DDX58 1 DOCK8 8 EGR1 1 EPG5 3 ETF1 1 FPR2 1 GATA2 2 GFI1 4HIVEP1 1 HIVEP2 2 HTR2A 1 IDO2 1 IFIH1 3 IFNGR2 1 IFNLR1 1 IGLL1 0 IKBKB1 IL17F 1 IL1B 1 IL21R 1 IRAK4 2 ITSN2 2 JUN 2 KAT6B 1 KCTD7 1 LIG4 1LRBA 1 MALL 1 MAPK3 2 MAVS 0 MCEE 1 MKL1 1 MYD88 1 NBN 1 NFKB1 3 NOD2 6NRIP1 1 PIAS1 1 PIAS2 1 PIK3CD 4 PIK3CD-AS1 1 PIK3R1 1 PKHD1 3 PLCG2 5PNPT1 1 POLA1 1 POLE 1 PRF1 1 PRKCB 1 PRKCD 1 PRKCH 1 PRKDC 4 PSTPIP1 1PTEN 1 PTPRC 2 RABGEF1 1 RAD51 1 RAG1 4 RAG2 2 RIPK1 1 RIPK3 2 RNF168 2RTEL1 2 SHARPIN 1 SKIV2L 1 SMAD4 1 STIM1 2 STIM2 1 STXBP2 3 TAP2 1 TBK12 TCIRG1 1 TICAM1 2 TLR3 2 TLR4 1 TNFRSF11A 10 TNFRSF13B 1 TNFRSF8 1TP53 1 TRAF3 1 TRAFD1 1 TRPM2 1 VPS45 1 WEE1 2 ZAP70 3 TOTAL (96 genes)172 Non-redundant cases 67 Dx yield for PML 95.7% cohort (n = 70)

The non-redundant number of PML cases and diagnostic yield are listed inthe last 2 rows of Table 19. Specifically, a test including the 96 geneshad a diagnostic yield of 95.7% based on the genetic findings from the70 PML cases used in the present study.

Example 16—Exemplary 39-Gene Panel PML Risk Prediction Tests

Table 20 contains an exemplary 39-gene panel based on genes that werefound to have multiple PML case count from Tables 7 and 8. The “Genes”and “Case level solutions” columns showed genes and total number of PMLcases (with at least two ‘case level’ solutions) reported in Tables 7and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2,SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values<0.05 (column O) were also included in Table 20. Among these 7 genes, 3genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’values <0.05 (column O) from Table 15.

TABLE 20 exemplary 39-gene panel Genes Case level solutions AP3B1 5 ATR3 CARD11 3 CHD7 4 DCLRE1C 3 DOCK8 8 EPG5 3 GATA2 2 GFI1 4 HIVEP2 2 IFIH13 IGLL1 0 IRAK4 2 ITSN2 2 JUN 2 MAPK3 2 MAVS 0 NFKB1 3 NOD2 6 PIK3CD 4PIKHD1 3 PLCG2 5 PRKDC 4 PTPRC 2 RAG1 4 RAG2 2 RIPK3 2 RNF168 2 RTEL1 2SHARPIN 1 STIM1 2 STXBP2 3 TBK1 2 TCIRG1 1 TICAM1 2 TLR3 2 TNFRSF11A 10WEE1 2 ZAP70 3 TOTAL (39 genes) 115 Non-redundant cases 57 Dx yield forPML cohort (n = 70) 81.4%

The non-redundant number of PML cases and diagnostic yield are listed inthe last 2 rows of Table 20. Specifically, a test including the 39 geneshad a diagnostic yield of 81.4% based on the genetic findings from the70 PML cases used in the present study.

Example 17—Exemplary 23-Gene Panel PML Risk Prediction Tests

Table 21 contains an exemplary 23-gene panel based on genes that werefound to have multiple PML case count from Tables 7 and 8. The “Genes”and “Case level solutions” columns showed genes and total number of PMLcases (with at least three ‘case level’ solutions) reported in Tables 7and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2,SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values<0.05 (column O) were also included in Table 21. Among these 7 genes, 3genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’values <0.05 (column O) from Table 15.

TABLE 21 exemplary 23-gene panel Genes Case level solutions AP3B1 5 ATR3 CARD11 3 CHD7 4 DCLRE1C 3 DOCK8 8 EPG5 3 GFI1 4 IFIH1 3 IGLL1 0 MAVS 0NFKB1 3 NOD2 6 PIK3CD 4 PKHD1 3 PLCG2 5 PRKDC 4 RAG1 4 SHARPIN 1 STXBP23 TCIRG1 1 TNFRSF11A 10 ZAP70 3 TOTAL (23 genes) 83 Non-redundant cases50 Dx yield for PML cohort (n = 70) 71.4%

The non-redundant number of PML cases and diagnostic yield are listed inthe last 2 rows of Table 21. Specifically, a test including the 23 geneshad a diagnostic yield of 71.4% based on the genetic findings from the70 PML cases used in the present study.

Example 18—Exemplary 15-Gene Panel PML Risk Prediction Tests

Table 22 contains an exemplary 15-gene panel based on genes that werefound to have multiple PML case count from Tables 7 and 8. The “Genes”and “Case level solutions” columns showed genes and total number of PMLcases (with at least four ‘case level’ solutions) reported in Tables 7and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2,SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values<0.05 (column O) were also included in Table 22. Among these 7 genes, 3genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’values <0.05 (column O) from Table 15.

TABLE 22 exemplary 15-gene panel Genes Case level solutions AP3B1 5 CHD74 DOCK8 8 GFI1 4 IFIH1 3 IGLL1 0 MAVS 0 NOD2 6 PIK3CD 4 PLCG2 5 PRKDC 4RAG1 4 SHARPIN 1 TCIRG1 1 TNFRSF11A 10 TOTAL (15 genes) 59 Non-redundantcases 39 Dx yield for PML cohort (n = 70) 55.7%

The non-redundant number of PML cases and diagnostic yield are listed inthe last 2 rows of Table 22. Specifically, a test including the 15 geneshad a diagnostic yield of 55.7% based on the genetic findings from the70 PML cases used in the present study.

Example 19—Exemplary 11-Gene Panel PML Risk Prediction Tests

Table 23 contains an exemplary 11-gene panel based on genes that werefound to have multiple PML case count from Tables 7 and 8. The “Genes”and “Case level solutions” columns showed genes and total number of PMLcases (with at least five ‘case level’ solutions) reported in Tables 7and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2,SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values<0.05 (column O) were also included in Table 23. Among these 7 genes, 3genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’values <0.05 (column O) from Table 15.

TABLE 23 exemplary 11-gene panel Genes Case level solutions AP3B1 5 CHD74 DOCK8 8 IFIH1 3 IGLL1 0 MAVS 0 NOD2 6 PLCG2 5 SHARPIN 1 TCIRG1 1TNFRSF11A 10 TOTAL (11 genes) 43 Non-redundant cases 33 Dx yield for PMLcohort (n = 70) 47.1%

The non-redundant number of PML cases and diagnostic yield are listed inthe last 2 rows of Table 23. Specifically, a test including the 11 geneshad a diagnostic yield of 47.1% based on the genetic findings from the70 PML cases used in the present study.

Example 20—Exemplary 10-Gene Panel PML Risk Prediction Tests

Table 24 contains an exemplary 10-SNV panel based on top 7 SNVs in Table14 and 3 SNVs from Table 15 (based on overlapping genes between 14 and15: IGLL1, MAVS, SHARPIN). Specifically, Using the top 10 SNVs (7 fromTable 14, along with 3 from Table 15, residing in genes already selectedfrom Table 14), an additive count (column “Case total additive(non-redundant)”) was performed to determine how many PML cases had atleast one of the variants when these were considered in order (e.g.,column “Order (FET)”: ‘1’, first, followed by ‘1’+‘2’, followed by‘1’+‘2’+‘3’, etc). Since some individuals harbor more than one variant,the additive count is not equal to the simple sum of PML case numbersfor each variant (column “Case total per SNV”). All genome coordinatesare based on hg19 build.

An additive count was performed for ExAC subjects (column “ExAC subjectstotal additive (redundant)”), as follows: i) The average cohort size forExAC for all variants was calculated; ii) Each total subject count (allethnicities) was normalized to this average cohort size. The ExACadditive count represents a simple addition: labeled as “redundant” incolumn “ExAC subjects total additive (redundant)”, because informationregarding the possible presence of multiple variants in the sameindividual is not available; iii) Odds Ratios (ORs) and Fisher's Exacttest (FET) values were calculated (columns “PML ALL OR additive” and“PML ALL FET additive”).

TABLE 24 exemplary 10-gene panel ExAC Case Case total subjects PML PMLtotal additive Dx yield total ALL ALL Order Table Variant per (non-(non- additive OR FET (FET)¹ source Gene (hg19) Genotype SNV redundant)²redundant) (redundant)³ additive additive 1 14 PLCG2 chr16: 81942175,A > G het 7 7 10% 730 6.50 2.00E−04 2 14 IFIH1 chr2: 163136505, C > Ghet 7 13 19% 1,473 6.49 6.37E−07 3 14 TCIRG1 chr11: 67818269, G > A het4 16 23% 1,830 6.73 2.94E−08 4 14 IGLL1 chr22: 23917192, G > T het 8 2231% 3,388 5.42 9.41E−09 5 14 MAVS chr20: 3846397, C > T hom 8 26 37%4,947 4.60 2.13E−08 6 14 SHARPIN chr8: 145154222, G > A het 12 33 47%8,064 3.91 5.10E−08 7 14 CHD7 chr8: 61654298, T > A het 5 36 51% 9,2923.89 3.26E−08 8 15 SHARPIN chr8: 145154824, A > C het 3 37 53% 9,2944.12 8.10E−09 9 15 IGLL1 chr22: 23915745, G > A het 3 38 54% 9,394 4.302.59E−09 10 15 MAVS chr20: 3843027, C > A hom 6 38 54% 10,393 3.775.26E−08 ¹SNV order based on lowest FET value reported in Tables 14 and15 for combined ethnicities ²PML case total = 70 ³ExAC subject total =43,419 (average for the 10 SNVs)

It can be appreciated by those skilled in the art that the above genepanels were selected based on the present genetic findings in 70 PMLcases. Furthermore, a gene not presently selected for any of theseexemplary gene panels may be added to the gene panel. For example, genesin which only 1 PML case was found to have variants fulfilling thecriteria may be added to the gene panel if genetic validation inadditional PML cases shows a ‘n=1 case’ gene is impacted by more than 1PML case when the data are examined for a new set of PML cases. In somecases, additional genes (e.g., PML-linked genes such as DOCK8, BAG3,STAT1) may be added to the gene panel.

Example 21—Identify Additional Genetic Variations

The methods and protocols described in the previous examples can be usedto identify any possible genetic variations. Data can be generated bycomparing genetic variations identified in 2 cohorts: 1) non-diseasedcohort including 1000 non-diseased individuals (e.g., individualswithout PML); and 2) diseased cohort including 100 diseased individuals(e.g., individuals with PML). The individuals in the cohorts can begender and/or ethnically matched. The genetic variations present in thenon-diseased cohort and diseased cohort can be identified using CNVanalysis (e.g., described in Example 2) or whole exome sequencing (e.g.,described in Example 3). Two new genetic variations, CNV 1 (located ongene #1) and CNV 2 (located on gene #2), are identified, for example, bycomparing the sequence data with a reference sequence (e.g., UCSC hg19).Data from a CNV database created using genome-wide CNV data on healthysubjects (or individuals without PML) such as the Normal VariationEngine (NVE) described herein can be used to determine if a CNV found ina PML cohort occurs at higher frequency or not compared to the NVE.Similarly, SNVs identified in a PML cohort can be interpreted for thepotential relevance to PML using the Exome Aggregation Consortium (ExAC)or Genome Aggregation Database (gnomAD) publicly available resources[Lek M et al. Nature. 2016 Aug. 18; 536(7616):285-91]; that is, toobtain frequency data (e.g., ethnic-specific frequency) for variantsunder consideration. In other embodiments, NVE databases for CNVassessment can be created for a variety of ethnicities (e.g., Africanand Latino ancestry subjects) to determine relevance of a CNV in a PMLcohort compared to an ethnically matched CNV database on individualswithout PML and/or using ethnic-specific data from publicly availableCNV databases such as the Database of Genomic Variants [MacDonald J etal. Nucleic Acids Res. 2014 January; 42(Database issue):D986-92]. In oneexample, 20 out of the 100 diseased individuals have CNV 1, and only 10out of the 1000 non-diseased individuals have CNV 1. In another example,10 out of the 100 diseased individuals have CNV 2, and only 5 out of the1000 non-diseased individuals have CNV 2. The p-value can be calculatedusing standard tests, such as the Fisher's Exact Test (FET) and data canbe selected using certain significance value. For example, geneticvariations with a p-value of less than 0.05 are included. Further, thefrequency and odds ratio of the two genetic variations can be calculatedand summarized in an exemplary table:

Frequency Frequency in non- Genetic in diseased diseased variation Genescohort cohort OR CNV 1 Gene #1 20/100 = 10/1000 = (20/80) / (10/990) =20% 1% 24.75 CNV 2 Gene #2 10/100 = 5/1000 = (10/90) / (5/995) = 10%0.5% 22.11

A subject without CNV 1, CNV 2, or both, may have a decreased risk ofPML due to an infection of the brain by John Cunningham virus (JCV), andthus may be administered an immunosuppressive medication, such asnatalizumab.

Other genetic variations such as SNV can be identify using the samemethod as described above.

Example 22—Analysis of the PML Cohort Array CGH Data for Additional CNVs

The array CGH data on the 71 PML cases was assessed (70 of 71 cases havearray CGH and WES data, but PML67 only has array CGH data) to identifyrecurrent CNVs meeting the criteria of an OR >=3 and a FET <=0.05. Thebenefit of looking at higher frequency, recurrent CNVs is that PML riskcan be easily assessed with PCR based, high-throughput screening methodsthat are also cost-effective. More frequent CNVs also have the potentialto identify increased risk for PML in a larger proportion of patients,similar to the variant burden SNVs reported in multiple PML cases (e.g.,Tables 14, 15, 38, and 39). For example, a genetic variant panel testfor identifying a patient's risk of developing PML might contain one ormore CNVs from Tables 1 or 28A and/or one or more SNVs from Tables 14,15, 34, or 35.

Four recurrent losses of potential relevance in assessing PML risk werefound and are reported in Table 28A (GRCh36/hg18 genome coordinates),three of which are also reported in Table 28B. One loss impacts exonicregions of CFHR1 and CFHR3 (SEQ ID 2200) and two other losses occur inintronic regions of the genes FUT8 (SEQ ID 2203) and ZBTB20 (SEQ ID2202). The fourth loss is intergenic (SEQ ID 2201) and is locatedbetween two Ensembl genes (GRCh37/hg19 genome assembly): ENSG00000229703(Ensembl transcript variant ENST00000437830, which overlaps Refseq geneLOC101928226 and its corresponding RefSeq transcript NR 125950.1) andENSG00000232694 (Ensembl transcript variant ENST00000436484). While theintergenic deletion may be impacting the expression of one or bothadjacent genes (e.g., via loss of a transcription factor binding site),those skilled in the art will also consider whether long-rangeinteractions are involved such that expression levels of genes locatedfurther away are modulated up or down (e.g., see Mifsud B et al. 2015,PMID 25938943). Similarly, intronic variants may have a similar impactand there is also the possibility that genetic variants (SNPs/SNVs,CNVs, etc.) are not directly involved in modulating gene expression butare in linkage disequilibrium (LD) with other genetic variants that aredirectly causing an effect (e.g., such variants serve as tags of causalor protective variants).

It can be appreciated by those skilled in the art that genetic variants(CNVs, SNVs, etc.) can be found in multiple, independent studies andmany are reported in public databases, such as the Database of GenomicVariants (MacDonald J et al. 2014, PMID 24174537), the Exome AggregationConsortium (ExAC, see Lek M et al. 2016, PMID 27535533), and ClinVar(Landrum M et al. 2018, PMID 29165669). Recurrent CNVs (gains orlosses), such as those reported in Table 28A (and a subset that arereported in Table 1), are often found to approximately match thechromosomal breakpoints for CNVs reported from the 1000 GenomesConsortium Phase 3 study (Mills R et al. 2011, PMID 21293372; 1000Genomes Project Consortium 2015, PMID 26432245). Since the CGH array(Agilent, Santa Clara, Calif.; array design ID AMADID 021529) used forgenome-wide detection of CNVs in the PML cases contains ˜1 millionprobes each spaced ˜3 Kb apart, the breakpoints can each map anywherebetween the reported genomic locations of probes (Tables 1 and 28A) andthe next nearest probe. Use of publically available CNV data issometimes useful for mapping breakpoints via sequencing and designingassays when they are similar in size and location of the CNVs detectedin an independent study. For example, the three recurrent CNVs reportedin Table 28A are approximately the same and location as deletionreported in the 1000 Genomes Consortium Phase 3: SEQ ID 2200 is similarto esv3588469, SEQ ID 2201 is similar to esv3589567, SEQ ID 2202 issimilar to esv3597466, and SEQ ID 2203 is similar to esv3634776.

Table 28B lists the CNV Subregion Numbers (SRN, numbers 364-366) for thethree variants that are present as heterozygous and/or homozygous lossesand pass statistical filters, as described below. For CNVs that are notidentical, the CNV subregion corresponds to the overlapping portionswith other CNVs. In the case of recurrent CNVs, the CNV subregion may beidentical to the original CNV (e.g., as in Tables 28A and 28B). Table28B also contains the OR and FET values in the comparison of thefrequency of the CNV in NVE cases (e.g., control subjects that do nothave PML) vs. PML cases. The NVE cohort size is 1,000 subjects(unaffecteds) and the PML cohort size is 71 patients (affecteds). Allreported CNVs/CNV subregions in Table 28B had FET <0.004, which is wellbelow the 0.05 cutoff filter that was applied for this analysis. Thecorresponding OR values for the heterozygous losses (het loss) were 3.61to 32.62 and for the homozygous losses (hom loss) were 42.57 to 71.98,which all are greater than the OR cutoff of 3. Tables 29 and 30 containthe gene and transcript variant information for the Table 28A genes thatare directly impacted by a CNV (FUT8 and ZBTB20) except for the CFHR1and CFHR3 genes, which are reported on in Tables 31 and 32.

Immune Dysregulation Genes

Immune dysregulation disorders, which are one of the underlying factorsof PML (Hatchwell E 2015, PMID 26029204), are caused by mutations in oneor more genes. Numerous genes have already been reported in theliterature (e.g., NCBI PubMed) or other public databases (e.g., OMIM)and new ones continue to be discovered. Consequently, a state-of-the-artcomprehensive genetic risk prediction test for PML will periodicallyinvolve assessment of information in the field for newly reported immunedysregulation genes, as well as performing new discovery studies (e.g.,using a CNV-based gene discovery approach, as described herein, on a newcohort of PML cases). Furthermore, newly discovered genes linked to adisease or condition are oftentimes independently validated by otherstudies. For example, in our first PML study, our discovery of ahomozygous deletion (SEQ ID 1028) upstream of ITSN2 (GN 309) as apotential cause of a PML patient's underlying immunodeficiency conditionwas subsequently supported by evidence in a mouse model that this geneis involved in immune dysregulation (Burbage M et al. 2018, PMID29337666).

Our original PML risk gene/variant discovery study involved assessmentof a total of 435 genes (see Tables 3, 6, 25A, 25B, and 26). Thepublished literature was reassessed for new genes that cause orcontribute to immune dysregulation disorders and a curated list of 270genes was assembled (see Table 31). For example, one source for newgenes to consider in our PML cohort was derived from a December, 2017update by the International Union of Immunological Societies (IUIS) onprimary immunodeficiencies (Bousfiha A et al. 2017, PMID 29226301;Picard C et al. 2017, PMID 29226302), which described 334 genes linkedto inborn errors of immunity and 137 of these were not included in ouroriginal gene lists (Tables 3, 6, 25A, 25B, and 26). Another source wasa study of common variable immunodeficiency genes (CVID) and review ofthe literature (de Valles-Ibanez G et al. 2017, PMID 29867916), whichdescribed 92 genes and 40 were not included in our original list of 435genes. Interestingly, 37 of these 92 genes were not included in theupdated IUIS list (PMIDs 29226301 and 29226302), which underscores theimportance of consulting multiple, independent sources when curating anupdated list of new immune dysregulation genes to consider. One othermajor source of new genes that comprise our set of 270 genes was anexome sequencing study on patients with primary antibody deficiency(PAD), a frequent form of primary immunodeficiency (PID). This study(Abolhassani H et al. 2018, PMID 29921932) assessed 202 genes of which76 genes were not included in our original set of 435 genes and 45 ofthe 202 genes were not included in the updated IUIS list (PMIDs 29226301and 29226302). The role of complement genetics in immune dysregulationdisorders has been discussed (Mayilyan K 2012, PMID 22773339). Somecomplement system genes were already assessed in our original set of PMLgenes (e.g., C1QA, C1QB, C1QC, C5AR1, CD55, CD59, CR2, and FCN3 listedin Table 6) and 30 new ones were included in the new set of immunedysregulation genes (Table 31, see genes annotated with PMID 22773339).

Since another key underlying factor of PML is infection with the JCvirus (Hatchwell E 2015, PMID 26029204), we also reassessed theliterature and other sources (e.g., interactions via the String db,Szklarczyk D et al. 2017, PMID 27924014) for JCV-related biology andcorresponding genes. For example, this was previously done to identifycandidate PML risk genes (e.g., as described by van der Kolk N et al.2016, PMID 27042682) in which a subset was subsequently found to harborrare variants in one or more PML cases in our study (see Table 27, JCvirus biology column). This new assessment resulted in inclusion of 18new genes that are linked to JCV biology: B2M, BRD4, CXCR3, CXCL10,HERC5, IF135, IFIT2, IFIT3, IGHMBP2, MX1, MX2, OAS1, OAS2, OAS3, OASL,RELA, RSAD2, XAF1. Published source annotation for this set of genes arereported in Table 31. For example, the Type I interferon pathway, whichwas implicated as a factor in PML on the basis of genetic variants foundin genes involved in the pathway (e.g., IFIH1 and MAVS) in our priorstudy of the 70 PML cases (e.g., see Table 27), was linked to JCVbiology via String db analysis of other genes in the pathway (Assetta Bet al. 2016, PMID 27381292). In another example, supporting biology forthe OAS gene family was found in a study of HIV-associatedneurocognitive disorder (HAND) patients (Puccini J et al. 2015, PMID25834052; Sanfilippo C et al. 2018, PMID 28236279), which is anothertype of neurological disorder that can manifest in HIV patients (KolsonD 2018, PMID 28820724).

Potential links between Parkinson's Disease (PD) genes and PML werefurther explored since SNCA was in our first gene list (see Table 6) andour separate investigation of SNCA triplication breakpoints identifiedthe HERC5 and HERC6 genes as potentially relevant to PD (see Zafar F. etal. 2018, PMID 29928688; Im E et al. 2016, PMID 27534820). The potentialoverlap in pathological mechanisms between PML and PD is furtherunderscored by the link of HERC5 to JCV (Assetta B et al. 2016, PMID27381292) and neuroinflammation in general (Gelders G et al. 2018, PMID29850629). Our curation of independent PD studies (including our own) orreview papers have now linked a total of 37 PD-related genes to ourcandidate PML genes: 16 genes (CXCL12, CXCR4, DDX58, IFIH1, IL1B, MAVS,MYD88, RAB7A, RABGEF1, RAG1, SNCA, SQSTM1, TBK1, TLR3, TLR4, TMEM173) inour original list of 435 genes (Table 6) and 21 genes (ATG9A, CCZ1,FIS1, HERC5, HERC6, IFIT1, IFIT2, IFIT3, LRRK2, MFN1, MFN2, MON1A,MON1B, PINK1, PARK2/PRKN, RAB5A, RAB5B, RAB5C RSAD2, TBC1D15, TBC1D17)in our new list of 270 genes (Table 31). In addition to the previouslymentioned PD citations (PMIDs 29850629 and 29928688), supportingliterature for linking known and candidate PD genes to candidate PMLgenes include: Torres-Odio S et al. 2017, PMID 28768533; Yamano K et al.2018, PMID 29360040; Paparisto E et al. 2018, PMID 29669830. In Table31, the disease model for LRRK2 is listed as unknown since mutations inthis gene are not presently known to cause an immunodeficiency disorder(e.g., it does not appear in the updated IUIS gene lists, see PMIDs29226301 and 29226302). It is known to cause PD via an AD model but,without further studies, this cannot be assumed with respect to immunedysregulation in the context of other disorders. Interestingly, recentstudies (e.g., see Yan R and Liu Z 2017, PMID 27830463; Lee H et al.2017, PMID 28202666; Witoelar A et al. 2017, PMID 28586827; Hui K et al.2018, PMID 29321258; Sheng D et al. 2018, PMID 29499195; Toledo Pinto Tet al. 2018, PMID 29755459; Kim K et al. 2018, PMID 29760073)increasingly support a role for LRRK2 in immune function (e.g., Type Iinterferon pathway) and immune disorders (e.g., Crohn's disease andleprosy).

We also revisited the literature for any new findings related to genesin our original list of 419 candidate PML genes (Table 6) that werefound to harbor genetics variants of interest in our original analysisof the array CGH CNV data and/or WES data on the 70 PML cases in ourcohort. Supporting evidence (Magna M et al. 2014, PMID 24531836; Jiang Ret al. 2014, PMID 25339669; Minguet S et al. 2017, PMID 28805811;Ratajczak M et al. 2018, PMID 29541038; Lee G et al. 2018, PMID29674451) was found for TLR4-linked genes (CXCL12, CXCR4, MYD88) in ourprevious list of 435 genes (Table 6), plus two new genes (CAV1 andHMGB1) in our updated list of 270 genes (Table 31). Finally, MB21D1(gene alias cGAS) was added to our updated gene list (Table 31) on thebasis of its direct link to TMEM173 (gene alias STING), which wasincluded in our original gene list (Table 6); for example, ashighlighted in a recent review (Chen Q et al. 2016, PMID 27648547).Finally, ITSN1 was included in our list of 270 genes (Table 31) based ona supporting study (Burbage M et al. 2018, PMID 2933766), cited hereinas supporting functional data for one of our CNV-discovered PMLcandidate genes (ITSN2), plus three other more recent studies (Alvisi Get al. 2018, PMID 29599122; Dergai O et al. 2018, PMID 29851086;Gryaznova T et al. 2018, PMID 29958948).

It is well appreciated by those skilled in the art that many commondisorders have a genetic basis and can be caused by one (autosomal,X-linked dominant, or X-linked recessive) or two mutations (autosomalrecessive) in a gene, and that the mutation(s) may occur in any one ofnumerous genes. Furthermore, an increasing number of genetic studies arerevealing that a given disorder can be caused or modified (e.g., age ofonset or severity) by multiple variants present within a patient'sgenome. For example, autism has been linked to the presence of two ormore genetic variants (CNVs or SNVs) within an individual (Marshall C etal. 2008, PMID 18252227; Yuen R et al. 2015, PMID 25621899).Accumulating evidence suggests that a monogenic disease model for immunedysregulation also provides an incomplete explanation of the pathology.For example, de Valles-Ibanez et al. 2018 (PMID 29867916) discuss theimportance of considering other disease models (e.g., oligogenic orpolygenic), particularly since the majority of CVID patients remainundiagnosed despite genetic assessment with exome or whole genomesequencing approaches.

Based on advances in genetic sequencing technologies and rapidly growingdisease gene lists, many genetic testing providers now use gene paneltests, which are used to assess and deliver clinical information onlyfor the subset of genes that have been definitively reported to causethe disease. Gene panel tests can be performed by genome capture methodsfor just the genes of interest or by performing WES or WGS but onlyinterpreting the relevant disease genes (e.g., an in silico capture of asubset of the genes in the human genome). It can be appreciated by thoseskilled in the art that a PML genetic risk prediction test will likelyinvolve testing for deleterious genetic variants in several immunedysregulation genes and that new genes/variants may be added to thetesting panel as new studies are reported on immune disorder patientsand/or PML patients.

There are several genetic testing providers that now offer gene paneltesting. An example of a commercial provider of several differentdisease gene panels is Invitae (San Francisco, Calif.). Given theirexperience with testing and interpretation of a wide variety of genepanels (e.g., inherited cancers, metabolic disorders, and cardiologydisorders), we compared their set of immunology gene panels to ourcurated PML candidate gene lists (Tables 6 and 31) to determine if theirexisting gene panel could be one potential option for assessing thegenetic risk of developing PML. As of June 2018, Invitae had a total of210 genes in their immunology panels and 157 of these were alreadyincluded in our first list of 435 PML candidate genes (Tables 3, 6, 25A,25B, and 26) and 206 were present in IUIS's December, 2017 update onprimary immunodeficiencies (Bousfiha A et al. 2017, PMID 29226301;Picard C et al. 2017, PMID 29226302). However, 3 genes (ACD, PMM2, andSLC7A7) in Invitae's immunology gene panels were not found in ourCNV-based gene discovery studies or in the various curation resourcesdescribed herein. Therefore, for completeness, we included these 3 genesin our updated panel of 270 genes (Table 31).

There are 9 genes in Table 31 that have had gene symbol changes sincethe PML WES data were generated, these are (current RefSeq gene symbollist first and WES data gene symbol second):

ADA2 CECR1 ADGRL2 LPHN2 CXCL8 IL8 FAAP24 C19orf40 NSMCE3 NDNL2 OTULINFAM105B PRKN PARK2 STN1 OBFC1 WASHC5 KIAA0196

Transcript variants and SEQ ID numbers for the additional 270 immunedysregulation genes (Table 31) are reported in Table 32. No RefSeqtranscript variants were found for the IGHM and IGKC genes, so these areomitted from Table 32.

Analysis of the PML Cohort WES Data for 270 Additional ImmuneDysregulation Genes

Using our previous methods for mining genetic variants from WES data on70 PML cases (described herein), we have identified several new variantsin a subset of the 270 genes (see Tables 32-37, 38, and 39) that may becausing or contributing to a PML patient's immune-compromised condition.As was done for the original 435 immune dysregulation genes (Tables 3,6, 25A, 25B, and 26), three types of genetic analysis methods were usedfor the new set of 270 genes (Table 31): 1) case-solving approach, 2)gene burden analysis, and 3) variant burden analysis. A total of 275SNVs (see Table 33) in 113 of the 270 genes that were assessed wereidentified in the cohort of 70 PML cases.

The case-solving method, which involves assessing WES data for each PMLpatient for the presence of rare, deleterious SNVs in comparison to anunselected control set of WES data (publicly available data from theExome Aggregation Consortium, exac.broadinstitute.org), was applied toall 70 PML cases for which WES data were collected (see Table 7 forSample ID, Ethnicity, Gender, and Primary Disease for each case). In thefirst study of this cohort that involved assessment of 435 genes (Tables3, 6, 25A, 25B, and 26), the case-solving findings were reported inTables 7-10 wherein Table 7 reported the top genetic variation(s) andgene for each case on the basis of variant frequency (<1 in 100frequency cutoff in comparison to the ExAC subjects) and the knownbiology of the gene at the time of the study. Additional potentialsolutions were reported in Tables 8-10. Given the growing evidence formultiple variants/genes causing or contributing to immune dysregulation,case-solving results for the 270 additional genes were partitioned into4 tables as follows:

-   -   Table 34, SNVs (het, hom, or phased comp het) with a frequency        of <=1/1,000 ExAC subjects or are novel;    -   Table 35, SNVs (het, hom, or phased comp het) with a frequency        of <=1/100 but >1/1,000 ExAC subjects;    -   Table 36, Un-phased het SNVs with a potential compound        heterozygous frequency of <=1/100 ExAC subjects (a subset may        prove to be in trans with further validation work);    -   wherein SNVs are referred to as heterozygous (het), homozygous        (hom), or compound heterozygous (comp het).

As before, the frequency information for each variant was assessed in anethnic-specific manner (AFR, EUR, or LAT). Variants were excluded fromthe analysis if the allele number in the ExAC subjects for a givenethnicity was <75% of the maximal number (˜10,300 for AFR subjects,˜11,300 for LAT subjects, or ˜66,500 for EUR subjects). An exception wasmade for variant CFHR3 chr1:196759282, C>T, which has lower AN but onlyin AFR ExAC subjects. Other studies have reported that a deletionimpacting CFHR3 is present at higher frequency in African ancestrysubjects (e.g., see Cantsilieris S et al. 2018, PMID 29686068).

We observed a recurrent CFHR3 deletion (˜56 Kb in size) in our NVEcontrol subjects and PML cases that maps to: chr1:196742735-196799244(GRCh37/hg19). Both heterozygous and homozygous losses were found butonly the homozygous deletions found in PML cases are reported in Table28A (SEQ ID 2200). The loss overlaps the 1000 Genomes Phase 3 deletionesv3588469 (˜80 Kb in size): chr1:196728877-196808865 (GRCh37/hg19). Itis possible that these two deletions are the same, which can be verifiedby sequencing the breakpoints of the deletion found in our NVE controlsand PML cases. We observed the CFHR3 deletion in the homozygous state in52 NVE controls (all EUR ancestry) and 5 PML cases (2 AFR and 1 LATancestry). Furthermore, we found a CFHR3 hom SNV in our variant burdenanalysis (described herein, see Table 38). Give the high frequency ofthe deletion in the general population, it is possible that someindividuals called as homozygotes for the SNV are compound heterozygotesfor the SNV and the deletion. The nature of short read sequencing meansthat homozygosity for a variant is inferred if a) the data is ofsufficient quality (sufficient number of reads present) and b) only oneof the two possible sequences at a given base position is observed.However, if an individual has only one allele (the other having beendeleted), there is only one possible ‘state’ at each given base. This isknown as loss of heterozygosity and is distinct from homozygosity. Forthis reason, the analysis of the homozygous state for the SNV has to betreated cautiously. However, the compound heterozygous state (SNV plusdeletion) may well result in the same functional consequences as thehomozygous SNV. Further laboratory work would be required to deconvolutethe genotypes in this cohort.

Interestingly, the CFHR3 deletion has been linked to atypical hemolyticuremic syndrome (aHUS), as described in a recent case report (Bitzan M.et al. 2018, PMID 29728803). Furthermore, a 2015 case report(Gomez-Cibeira E et al. 2015, PMID 26718572) links aHUS to PML. Nogenetic information was reported for this aHUS patient, but shedeveloped PML after receiving eculizumab.

A recessive or dominant disease model was applied according to theinformation reported in Table 31. For genes that have an ‘unknown’ or‘association’ entry, the disease model was assumed to be AD and/or AR.Furthermore, if an AD model is currently the standard for a given gene(e.g., in OMIM), we did not rule out the potential for an AR model. Forexample, MBL2 is reported in Table 31 as an AD model gene but Table 34reports on a rare homozygous (om) SNV (amino acid change G57E) in thePML15 case. The frequency cutoff of <1 in 100 was relaxed for FAT4 SNVA807V (SEQ ID 3086) in Tables 35 and 36 since this variant is present asa solution for multiple PML cases (PMLO9, PML28, PML31, PML32, PML37,PML65) in Table 34. In instances wherein a PML case had 3 or more SNVs,the frequency calculations were as follows: a) for a hom SNV paired withmultiple het SNVs (e.g., obligate comp hets), the pairwise frequency wascalculated for the hom SNV and each het SNV, and b) for 3 or more hetSNVs, pairwise frequency was calculated using the rarest SNV paired witheach higher frequency SNV.

Gene and variant burden analyses were performed on the updated set of270 genes (Table 31) according to the methods described herein for theoriginal set of 435 genes (Tables 3, 6, 25A, 25B, and 26). The resultsare reported in the following tables:

-   -   Table 37, gene burden results (same criteria used to generate        the Table 13 results);    -   Table 38, variant burden results (same criteria used to generate        the Table 14 results);    -   Table 39, variant burden results (same criteria used to generate        the Table 15 results);

The top SNV in Table 38 is CFHR3 chr1:196759282, C>T (rs138675433 indbSNP build 150). The genotype is homozygous in 3 AFR and 3 EUR ancestryPML cases. Therefore, we have found a homozygous deletion (SEQ ID 2200)and a homozygous SNV (SEQ ID 3025) impacting the CFHR3 gene. Both thedeletion and SNV are present at higher frequency in AFR ancestrysubjects. Therefore, genotyping both variants in control subjects andPML patients of different ancestries will help define their role inincreasing or decreasing PML risk. This is potentially highly relevantin light of a PML case report on a patient that had aHUS (Gomez-CibeiraE et al. 2015, PMID 26718572) and the link between aHUS and the CFHR3gene (Pouw R et al. 2018, PMID 29740447).

Genetic findings in the first set of 435 genes for the 70 PML cases weresummarized in a variety of formats (see Tables 7-10 and 13-27). Geneticfindings in the updated set of 270 genes are summarized in Table 40 forall three analysis methods. For some PML cases, an SNV can appear inmore than one case solving table (Tables 34-36), such as when an‘unknown’ disease model gene has 2 or more SNVs and a given SNV isascribed an AD model solution and an AR model solution. However, thetotal PML case counts in Table 40 correspond to a non-redundant numberof PML cases to accurately reflect the total number of potentiallysolved PML cases per gene.

One of the top genes summarized in Table 40 is FAT4, which is the onlygene that has genetic findings reported for all three types of analysis(case-solving, gene burden, variant burden) as reported in Tables 34-39.The FAT4 gene also has the highest number of potentially solved PMLcases, 23 solutions based on Tables 34-36. Other genes with a highernumber of case-solving solutions are: PRRC2A (22 solutions), MSH5 (9solutions), LRRK2 (8 solutions), and MX1 (8 solutions). Autosomalrecessive mutations in the FAT4 gene (OMIM 612411) are involved in twodisorders: Hennekam lymphangiectasia-lymphedema syndrome 2 (OMIM 616006)and Van Maldergem syndrome 2 (OMIM 615546). Hennekamlymphangiectasia-lymphedema syndrome 2 is of particular interest since aclinical feature of these patients is intestinal lymphangiectasia, whichhas been reported in a case of PML (Gomez-Cibeira E et al. 2015, PMID26718572), which is also noted herein for the link to the CFHR3 gene viathe PML patient's aHUS condition.

Another top gene in Table 40 is LRRK2, which has 8 solutions based onTables 34-36 and was significant in gene burden analysis (Table 37).LRRK2 variants (e.g., the G2019S gain-of-function mutation) wereinitially found to cause or contribute to Parkinson's Disease (PD), butadditional studies have linked the LRRK2 gene to immune function anddisorders, as reported herein and in Table 31 (see PMID citations). Wealso found a subset of PML patients harboring a pair of LRRK2 SNVs(N299K, also known as N55K, SEQ ID 3192; R1398H, SEQ ID 3197), withheterozygous or homozygous genotype (see Tables 34 and 35), that arereported to be protective against PD (e.g., see Ross 0 et al. 2011, PMID21885347; Heckman M et al. 2014, PMID 23962496; Heckman M et al. 2016,PMID 27521182). Whether one or both variants modify PML risk willrequire further studies.

TABLE 28A SEQ ID 2200-2203, four recurrent CNVs Original OriginalOriginal PML RefSeq CNV CNV CNV CNV Case Gene SEQ Chr Start Stop SizeType ID Symbol ID 1 195009358 195065867 56509 hom 3143 CFHR1, 2200 lossCFHR3 1 195009358 195065867 56509 hom 3159 CFHR1, 2200 loss CFHR3 1195009358 195065867 56509 hom 3193 CFHR1, 2200 loss CFHR3 1 195009358195065867 56509 hom 3202 CFHR1, 2200 loss CFHR3 1 195009358 19506586756509 hom 3273 CFHR1, 2200 loss CFHR3 1 246933929 246940630 6701 het3009 2201 loss 1 246933929 246940630 6701 het 3125 2201 loss 1 246933929246940630 6701 het 3152 2201 loss 1 246933929 246940630 6701 het 31732201 loss 1 246933929 246940630 6701 het 3175 2201 loss 1 246933929246940630 6701 het 3188 2201 loss 1 246933929 246940630 6701 het 31932201 loss 1 246933929 246940630 6701 het 3202 2201 loss 1 246933929246940630 6701 het 3203 2201 loss 1 246933929 246940630 6701 het 32052201 loss 1 246933929 246940630 6701 hom 3163 2201 loss 1 246933929246940630 6701 hom 3273 2201 loss 3 116140997 116146946 5949 het 3009ZBTB20 2202 loss 3 116140997 116146946 5949 het 3144 ZBTB20 2202 loss 3116140997 116146946 5949 het 3152 ZBTB20 2202 loss 3 116140997 1161469465949 het 3154 ZBTB20 2202 loss 3 116140997 116146946 5949 het 3159ZBTB20 2202 loss 3 116140997 116146946 5949 het 3192 ZBTB20 2202 loss 3116140997 116146946 5949 het 3194 ZBTB20 2202 loss 3 116140997 1161469465949 het 3200 ZBTB20 2202 loss 3 116140997 116146946 5949 het 3273ZBTB20 2202 loss 3 116140997 116146946 5949 hom 3173 ZBTB20 2202 loss 1465143023 65145120 2097 het 3006 FUT8 2203 loss 14 65143023 65145120 2097het 3010 FUT8 2203 loss 14 65143023 65145120 2097 het 3160 FUT8 2203loss 14 65143023 65145120 2097 het 3178 FUT8 2203 loss 14 6514302365145120 2097 het 3183 FUT8 2203 loss 14 65143023 65145120 2097 het 3189FUT8 2203 loss 14 65143023 65145120 2097 het 3194 FUT8 2203 loss 1465143023 65145120 2097 het 3201 FUT8 2203 lossTable 28A lists recurrent CNVs of interest in this study.

TABLE 28B SRN 364-366, three recurrent CNVs with values of OR >= 3 andFET <= 0.05 (SRN = original CNV since these are recurrent CNVs) CNV CNVCNV CNV Sub- Sub- Sub- Sub- PML Ref-Seq Exon region region region regionCNV Case Gene Over- NVE PML No. Chr Start Stop Size Type ID Symbol lapCases Cases FET OR (SRN) 1 246933929 246940630 6701 het loss 3009 N 5 102.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3125 N 5 102.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3152 N 5 2.02E−0932.62 364 1 246933929 246940630 6701 het loss 3173 N 5 10 2.02E−09 32.62364 1 246933929 246940630 6701 het loss 3175 N 5 10 2.02E−09 32.62 364 1246933929 246940630 6701 het loss 3188 N 5 10 2.02E−09 32.62 364 1246933929 246940630 6701 het loss 3193 N 5 10 2.02E−09 32.62 364 1246933929 246940630 6701 het loss 3202 N 5 10 2.02E−09 32.62 364 1246933929 246940630 6701 het loss 3203 N 5 10 2.02E−09 32.62 364 1246933929 246940630 6701 het loss 3205 N 5 10 2.02E−09 32.62 364 1246933929 246940630 6701 hom loss 3163 N 0 2 0.004453 71.98 364 1246933929 246940630 6701 hom loss 3273 N 0 2 0.004453 71.98 364 3116140997 116146946 5949 het loss 3009 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 het loss 3144 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 het loss 3152 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 het loss 3154 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 het loss 3159 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 het loss 3192 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 het loss 3194 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 het loss 3200 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 het loss 3273 ZBTB20 N 23 9 0.000122 6.17 365 3116140997 116146946 5949 hom loss 3173 ZBTB20 N 0 1 0.004453 42.57 36514 65143023 65145120 2097 het loss 3006 FUT8 N 34 8 0.004761 3.61 366 1465143023 65145120 2097 het loss 3010 FUT8 N 34 8 0.004761 3.61 366 1465143023 65145120 2097 het loss 3160 FUT8 N 34 8 0.004761 3.61 366 1465143023 65145120 2097 het loss 3178 FUT8 N 34 8 0.004761 3.61 366 1465143023 65145120 2097 het loss 3183 FUT8 N 34 8 0.004761 3.61 366 1465143023 65145120 2097 het loss 3189 FUT8 N 34 8 0.004761 3.61 366 1465143023 65145120 2097 het loss 3194 FUT8 N 34 8 0.004761 3.61 366 1465143023 65145120 2097 het loss 3201 FUT8 N 34 8 0.004761 3.61 366Table 28B lists CNVs/CNV subregions of interest with OR and FET values.

TABLE 29 GN 491 and 492, NCBI Gene ID, descriptions, RefSeq summary for2 of 3 Table 28A genes RefSeq Gene Gene Exon NCBI No. Symbol OverlapGene ID Gene Description RefSeq Summary (GN) FUT8 intronic 2530alpha-(1,6)- This gene encodes an enzyme belonging to 491fucosyltransferase the family of fucosyltransferases. The isoform aproduct of this gene catalyzes the transfer of fucose from GDP-fucose toN-linked type complex glycopeptides. This enzyme is distinct from otherfucosyltransferases which catalyze alpha1-2, alpha1-3, and alpha1-4fucose addition. The expression of this gene may contribute to themalignancy of cancer cells and to their invasive and metastaticcapabilities. Alternative splicing results in multiple transcriptvariants. [provided by RefSeq, May 2011]. Transcript Variant: Thisvariant (1, also known as B6) represents the longest transcript andencodes the longer isoform (a). Variants 1 and 3 encode the sameisoform. Sequence Note: This RefSeq record was created from transcriptand genomic sequence data to make the sequence consistent with thereference genome assembly. The genomic coordinates used for thetranscript record were based on transcript alignments. Publication Note:This RefSeq record includes a subset of the publications that areavailable for this gene. Please see the Gene record to access additionalpublications. Transcript exon combination :: AJ536056.1, AJ536054.1[ECO: 0000332] RNAseq introns :: single sample supports all intronsERS025084, ERS025088 [ECO: 0000348] ZBTB20 intronic 26137 zinc fingerand N/A 492 BTB domain- containing protein 20 isoform 1Table 29 lists gene information for genes in Table 28B

TABLE 30 SEQ ID 2204-2215, transcript variants for Table 29 genes (FUT8and ZBTB20, third CNV is intergenic) RefSeq RefSeq Gene Exon AccessionSEQ Symbol Overlap Number mRNA Description ID FUT8 intronic NM 004480Homo sapiens fucosyltransferase 8 (alpha (1, 6) 2204 fucosyltransferase)(FUT8), transcript variant 4, mRNA. FUT8 intronic NM 178155 Homo sapiensfucosyltransferase 8 (alpha (1, 6) 2205 fucosyltransferase) (FUT8),transcript variant 1, mRNA. FUT8 intronic NM 178156 Homo sapiensfucosyltransferase 8 (alpha (1, 6) 2206 fucosyltransferase) (FUT8),transcript variant 3, mRNA. FUT8 intronic NR 038167 Homo sapiensfucosyltransferase 8 (alpha (1, 6) 2207 fucosyltransferase) (FUT8),transcript variant 5, non- coding RNA. FUT8 intronic NR 038170 Homosapiens fucosyltransferase 8 (alpha (1, 6) 2208 fucosyltransferase)(FUT8), transcript variant 2, non- coding RNA. ZBTB20 intronic NM001164343 Homo sapiens zinc finger and BTB domain containing 2209 20(ZBTB20), transcript variant 3, mRNA. ZBTB20 intronic NM 015642 Homosapiens zinc finger and BTB domain containing 2210 20 (ZBTB20),transcript variant 2, mRNA. ZBTB20 intronic NM 001164342 Homo sapienszinc finger and BTB domain containing 2211 20 (ZBTB20), transcriptvariant 1, mRNA. ZBTB20 intronic NM 001164347 Homo sapiens zinc fingerand BTB domain containing 2212 20 (ZBTB20), transcript variant 7, mRNA.ZBTB20 intronic NM 001164346 Homo sapiens zinc finger and BTB domaincontaining 2213 20 (ZBTB20), transcript variant 6, mRNA. ZBTB20 intronicNM 001164344 Homo sapiens zinc finger and BTB domain containing 2214 20(ZBTB20), transcript variant 4, mRNA. ZBTB20 intronic NM 001164345 Homosapiens zinc finger and BTB domain containing 2215 20 (ZBTB20),transcript variant 5, mRNATable 30 represents a non-redundant list of transcript variants thatcorrespond to the Table 29 genes

TABLE 31 GN 493-762, 270 candidate PML genes, updated list from variouspublic databases (e.g., PubMed) RefSeq Gene Disease Gene Number SymbolModel Gene Source Source Annotation (GN) ACD AD AR Public db PMID:25205116, 25233904, 26810774 493 ACTB AD Public db PMID: 29226301,29226302 494 ACTN4 AD Public db PMID: 29921932 495 ADA2 AR Public dbPMID: 29226301, 29226302, 29867916 496 ADAM17 AR Public db PMID:29226301, 29226302 497 ADGRL2 unknown Public db PMID: 29921932 498 AIREAD AR Public db PMID: 29226301, 29226302, 29867916 499 ANP32B unknownPublic db PMID: 29867916 500 AP1S3 AR Public db PMID: 29226301, 29226302501 ARPC1B AR Public db PMID: 29226301, 29226302 502 ATG12 unknownPublic db PMID: 28141795, 28295214 503 ATG16L1 association Public dbPMID: 28141795 504 ATG5 AR Public db PMID: 28141795, 28295214 505 ATG7unknown Public db PMID: 28141795 506 ATG9A unknown Public db PMID:28768533, 29360040, 29669830, 507 29928688 ATP6AP1 XLR Public db PMID:29226301, 29226302 508 B2M AR Public db PMID: 27381292, 29226301,29226302 509 BCL11B AD Public db PMID: 29226301, 29226302 510 BCL2association Public db PMID: 29867916 511 BLK AD Public db PMID:29867916, 29921932 512 BRD4 unknown Public db PMID: 27007123, 29475942513 BTLA unknown Public db PMID: 29867916 514 C1R AR Public db PMID:29226301, 29226302, 22773339 515 C1S AR Public db PMID: 29226301,29226302, 22773339 516 C2 AR Public db PMID: 29226301, 29226302,22773339 517 C3 AD AR Public db PMID: 29226301, 29226302, 22773339 518C4A AR Public db PMID: 29226301, 29226302, 22773339 519 C4B AR Public dbPMID: 29226301, 29226302, 22773339 520 C5 AR Public db PMID: 29226301,29226302, 22773339 521 C6 AR Public db PMID: 29226301, 29226302,22773339 522 C7 AR Public db PMID: 29226301, 29226302, 22773339 523 C8AAR Public db PMID: 29226301, 29226302, 22773339 524 C8B AR Public dbPMID: 29226301, 29226302, 22773339 525 C8G AR Public db PMID: 29226301,29226302, 22773339 526 C9 AR Public db PMID: 29226301, 29226302,22773339 527 CAD AR Public db PMID: 29921932 528 CAMLG unknown Public dbPMID: 29921932 529 CARD14 AD Public db PMID: 29226301, 29226302 530CASP10 AD Public db PMID: 29226301, 29226302 531 CAV1 AD Public db PMID:24531836, 25339669, 28805811, 532 29541038, 29674451 CCBE1 AR Public dbPMID: 29226301, 29226302 533 CCDC22 XLR Public db PMID: 29921932 534CCZ1 unknown Public db PMID: 28768533, 29360040, 29669830, 535 29928688CD22 unknown Public db PMID: 29867916 536 CD274 unknown Public db PMID:29867916 537 CD276 unknown Public db PMID: 29867916 538 CD36 AR Publicdb PMID: 29921932 539 CD37 unknown Public db PMID: 29867916 540 CD38unknown Public db PMID: 29867916 541 CD46 AD Public db PMID: 29226301,29226302, 22773339 542 CD5 unknown Public db PMID: 29867916 543 CD70 ARPublic db PMID: 29226301, 29226302 544 CD72 unknown Public db PMID:29867916 545 CD74 unknown Public db PMID: 29867916 546 CD84 unknownPublic db PMID: 29867916 547 CD93 unknown Public db PMID: 29867916,22773339 548 CEBPE AR Public db PMID: 27042682, 29226301, 29226302 549CFB AD AR Public db PMID: 29226301, 29226302, 22773339 550 CFD AR Publicdb PMID: 29226301, 29226302, 22773339 551 CFH AD AR Public db PMID:29226301, 29226302, 22773339 552 CFHR1 AD AR Public db PMID: 29226301,29226302, 22773339 553 CFHR2 AD AR Public db PMID: 29226301, 29226302,22773339 554 CFHR3 AD AR Public db PMID: 29226301, 29226302, 22773339555 CFHR4 AD AR Public db PMID: 29226301, 29226302, 22773339 556 CFHR5AD AR Public db PMID: 29226301, 29226302, 22773339 557 CFI AD AR Publicdb PMID: 29226301, 29226302, 22773339 558 CFP XLR Public db PMID:29226301, 29226302, 22773339 559 CFTR AR Public db PMID: 29226301,29226302 560 CHD2 AD Public db PMID: 29921932 561 CLEC16A unknown Publicdb PMID: 29867916, 29921932 562 CLPB AR Public db PMID: 29226301,29226302 563 COPA AD Public db PMID: 29226301, 29226302 564 CSF2RA XLRPublic db PMID: 29226301, 29226302 565 CSF2RB AR Public db PMID:29226301, 29226302 566 CTC1 AR Public db PMID: 29226301, 29226302 567CXCL1 unknown Public db PMID: 28681388 568 CXCL10 unknown Public dbPMID: 23086711, 28237728 569 CXCL5 unknown Public db PMID: 28681388 570CXCL8 unknown Public db PMID: 28681388 571 CXCR3 unknown Public db PMID:28237728 572 CYBA AR Public db PMID: 29226301, 29226302 573 DCLRE1B ARPublic db PMID: 29226301, 29226302 574 DNAJC21 AR Public db PMID:29226301, 29226302 575 DNASE1L3 AR Public db PMID: 29226301, 29226302576 DNASE2 unknown Public db PMID: 29226301, 29226302 577 EBF1 unknownPublic db PMID: 29921932 578 EGF association Public db PMID: 29921932579 ERCC6L2 AR Public db PMID: 29226301, 29226302 580 EXTL3 AR Public dbPMID: 29226301, 29226302 581 FAAP24 AR Public db PMID: 29226301,29226302 582 FADD AR Public db PMID: 29226301, 29226302 583 FAT4 ARPublic db PMID: 29226301, 29226302 584 FCER2 unknown Public db PMID:29867916 585 FERMT3 AR Public db PMID: 29226301, 29226302 586 FIS1unknown Public db PMID: 28768533, 29360040, 29669830, 587 29928688 G6PDXLD Public db PMID: 29226301, 29226302 588 G1NS1 AR Public db PMID:29226301, 29226302 589 HERC5 unknown Public db PMID: 27381292, 28768533,29360040, 590 29669830, 29928688 HERC6 unknown Public db PMID: 28768533,29360040, 29669830, 591 29928688 HMGB1 unknown Public db PMID: 24531836,25339669, 28805811, 592 29541038, 29674451 HMOX1 AR Public db PMID:29226301, 29226302 593 HYOU1 AR Public db PMID: 29226301, 29226302 594ICAM1 association Public db PMID: 29921932 595 ICOSLG unknown Public dbPMID: 29867916 596 IFI35 unknown Public db PMID: 27381292, 28236279 597IFIT1 unknown Public db PMID: 28236279, 28768533, 29360040, 59829669830, 29928688 IFIT2 unknown Public db PMID: 27381292, 28236279,28768533, 599 29360040, 29669830, 29921932, 29928688 IFIT3 unknownPublic db PMID: 27381292, 28236279, 28768533, 600 29360040, 29669830,29928688 IGHM AR Public db PMID: 29226301, 29226302, 29867916 601IGHMBP2 AR Public db PMID: 1714899, 9034313, 11889755, 602 28202949,29272405 IGKC AR Public db PMID: 29226301, 29226302, 29867916 603 IL17RCAR Public db PMID: 29226301, 29226302 604 IL1RN AR Public db PMID:29226301, 29226302 605 IL3 unknown Public db PMID: 29867916 606 IL36RNAR Public db PMID: 29226301, 29226302 607 IL4 unknown Public db PMID:29867916 608 INO80 AR Public db PMID: 29226301, 29226302 609 INPP5Dunknown Public db PMID: 29921932 610 IRAK1 XLR Public db PMID: 29226301,29226302 611 IRF2BP2 AD Public db PMID: 29226301, 29226302, 29867916 612ITCH AR Public db PMID: 28295214, 29226301, 29226302, 613 29867916 ITGAMassociation Public db PMID: 29921932, 22773339 614 ITGB2 AR Public dbPMID: 29226301, 29226302, 22773339 615 ITPKB unknown Public db PMID:29921932 616 ITSN1 unknown Public db PMID: 29337666, 29599122, 29851086,617 29958948 JAK1 AD AR Public db PMID: 27648547, 29226301, 29226302 618KDM6A XLD XLR Public db PMID: 29226301, 29226302 619 KMT2D AD Public dbPMID: 29226301, 29226302 620 KRAS AD Public db PMID: 29921932 621 LAT ARPublic db PMID: 29226301, 29226302 622 LPIN2 AR Public db PMID:29226301, 29226302 623 LRRK2 unknown Public db PMID: 26844546, 27830463,28202666, 624 28768533, 29321258, 29360040, 29499195, 29669830,29755459, 29760073, 29850629 MAP3K14 AR Public db PMID: 29226301,29226302 625 MASP2 AR Public db PMID: 29226301, 29226302, 22773339 626MB21D1 unknown Public db PMID: 27648547 627 MBL2 AD Public db PMID:29867916, 22773339 628 MCM4 AR Public db PMID: 29226301, 29226302 629MCM5 AR Public db PMID: 29921932 630 MDC1 unknown Public db PMID:29921932 631 MEF2C AD Public db PMID: 29921932 632 MEFV AD AR Public dbPMID: 29226301, 29226302 633 MFN1 unknown Public db PMID: 28768533,29360040, 29669830, 634 29928688 MFN2 AD AR Public db PMID: 28768533,29360040, 29669830, 635 29928688 MLH1 AD AR Public db PMID: 29867916,29921932 636 MMP9 association Public db PMID: 28681388 637 MOGS ARPublic db PMID: 29226301, 29226302 638 MON1A unknown Public db PMID:28768533, 29360040, 29669830, 639 29928688 MON1B unknown Public db PMID:28768533, 29360040, 29669830, 640 29928688 MSH2 AD AR Public db PMID:29867916, 29921932 641 MSH5 AR Public db PMID: 29867916, 29921932 642MSH6 AR Public db PMID: 29226301, 29226302 643 MVK AD AR Public db PMID:29226301, 29226302 644 MX1 unknown Public db PMID: 27381292, 28236279645 MX2 unknown Public db PMID: 27381292, 28236279 646 MYSM1 AR Publicdb PMID: 29226301, 29226302 647 NBAS AR Public db PMID: 29226301,29226302 648 NCF1 AR Public db PMID: 29226301, 29226302 649 NCF2 ARPublic db PMID: 29226301, 29226302 650 NCF4 AR Public db PMID: 29226301,29226302 651 NCSTN AD Public db PMID: 29226301, 29226302 652 NFAT5 ADPublic db PMID: 29226301, 29226302 653 NHP2 AR Public db PMID: 29226301,29226302 654 NLRC4 AD Public db PMID: 29226301, 29226302 655 NLRP1 ARPublic db PMID: 29226301, 29226302 656 NLRP2 unknown Public db PMID:29921932 657 NLRX1 unknown Public db PMID: 28295214 658 NOD1 unknownPublic db PMID: 29921932 659 NOP10 AR Public db PMID: 29226301, 29226302660 NSMCE3 AR Public db PMID: 29226301, 29226302 661 OAS1 AR Public dbPMID: 27381292, 28236279 662 OAS2 unknown Public db PMID: 27381292,28236279 663 OAS3 unknown Public db PMID: 27381292, 28236279 664 OASLunknown Public db PMID: 27381292, 28236279 665 ORC4 AR Public db PMID:29867916, 29921932 666 OTULIN AR Public db PMID: 29226301, 29226302 667PARN AD AR Public db PMID: 26810774, 29226301, 29226302 668 PCCA ARPublic db PMID: 29921932 669 PCCB AR Public db PMID: 29921932 670 PDCD1association Public db PMID: 29867916 671 PDCD1LG2 unknown Public dbPMID: 29867916 672 PEPD AR Public db PMID: 29226301, 29226302 673 PINK1AR Public db PMID: 28768533, 29360040, 29669830, 674 29928688 PLAU ADPublic db PMID: 28681388 675 PLAUR unknown Public db PMID: 28681388 676PLCG1 unknown Public db PMID: 29921932 677 PLD1 AR Public db PMID:29921932 678 PLEKHM1 AR Public db PMID: 29226301, 29226302 679 PLK1unknown Public db PMID: 28295214 680 PLXNB1 unknown Public db PMID:29921932 681 PMM2 AR Public db PMID: 19862844, 24474243, 27415628 682POLE2 AR Public db PMID: 29226301, 29226302 683 PPM1A unknown Public dbPMID: 28295214 684 PRKN AR Public db PMID: 28768533, 29360040, 29669830,685 29928688 PRRC2A unknown Public db PMID: 29921932 686 PSEN1 AD Publicdb PMID: 29226301, 29226302 687 PSENEN AD Public db PMID: 29226301,29226302 688 PSMA7 unknown Public db PMID: 28295214 689 RAB5A unknownPublic db PMID: 28768533, 29360040, 29669830, 690 29928688 RAB5B unknownPublic db PMID: 28768533, 29360040, 29669830, 691 29928688 RAB5C unknownPublic db PMID: 28768533, 29360040, 29669830, 692 29928688 RAD50association Public db PMID: 29867916, 29921932 693 RANBP2 AD Public dbPMID: 29226301, 29226302 694 RASGRP1 AR Public db PMID: 29226301,29226302 695 RELA unknown Public db PMID: 27042682, 27648547 696 RELB ARPublic db PMID: 29226301, 29226302 697 RHOH AR Public db PMID: 29226301,29226302 698 RLTPR AR Public db PMID: 29226301, 29226302 699 RNF125 ADPublic db PMID: 28295214 700 RORC AR Public db PMID: 29226301, 29226302701 RPSA AD Public db PMID: 29226301, 29226302 702 RSAD2 unknown Publicdb PMID: 27381292, 28236279, 28768533, 703 29360040, 29669830, 29928688SAMD9 AD Public db PMID: 29226301, 29226302 704 SAMD9L AD Public dbPMID: 29226301, 29226302 705 SEMA3E AD Public db PMID: 29226301,29226302 706 SERP1NA1 AR Public db PMID: 29867916 707 SERPINB2 unknownPublic db PMID: 28681388 708 SERPING1 AD Public db PMID: 29226301,29226302, 22773339 709 SH3BP2 AD Public db PMID: 29226301, 29226302 710SLC29A3 AR Public db PMID: 29226301, 29226302 711 SLC35C1 AR Public dbPMID: 29226301, 29226302 712 SLC7A7 AR Public db PMID: 10655553,20301535 713 SLC9A1 AR Public db PMID: 29921932 714 SMARCAL1 AR Publicdb PMID: 29226301, 29226302 715 SMARCD2 AR Public db PMID: 29226301,29226302 716 SMC3 AD Public db PMID: 29921932 717 SMURF2 unknown Publicdb PMID: 28295214 718 SRP54 unknown Public db PMID: 29226301, 29226302719 STN1 AR Public db PMID: 29226301, 29226302 720 TBC1D15 unknownPublic db PMID: 28768533, 29360040, 29669830, 721 29928688 TBC1D17unknown Public db PMID: 28768533, 29360040, 29669830, 722 29928688 TCF3AD Public db PMID: 29226301, 29226302 723 TCN2 AR Public db PMID:29226301, 29226302 724 TEK AD Public db PMID: 29921932 725 TERC ADPublic db PMID: 29226301, 29226302 726 TERT AD AR Public db PMID:26810774, 29226301, 29226302 727 TFPI unknown Public db PMID: 28681388728 TFRC AR Public db PMID: 29226301, 29226302 729 THBD AD Public dbPMID: 28681388, 29226301, 29226302 730 THBS1 unknown Public db PMID:29921932 731 TINF2 AD Public db PMID: 26810774, 29226301, 29226302 732TIRAP AR Public db PMID: 29226301, 29226302 733 TMC6 AR Public db PMID:29226301, 29226302 734 TMC8 AR Public db PMID: 29226301, 29226302 735TNFRSF17 unknown Public db PMID: 29867916 736 TNFRSF1A AD Public dbPMID: 29226301, 29226302 737 TNFSF10 unknown Public db PMID: 29867916738 TNFSF13 unknown Public db PMID: 29867916 739 TNFSF13B unknown Publicdb PMID: 29867916 740 TNIP1 unknown Public db PMID: 29921932 741TP53AIP1 unknown Public db PMID: 29921932 742 TPP1 AD AR Public db PMID:29226301, 29226302 743 TPP2 AR Public db PMID: 29226301, 29226302 744TRAC AR Public db PMID: 29226301, 29226302 745 TRAF3IP2 AR Public dbPMID: 29226301, 29226302 746 TRIM25 unknown Public db PMID: 28295214 747TRIM37 AR Public db PMID: 29921932 748 TTC37 AR Public db PMID:29226301, 29226302 749 UBD unknown Public db PMID: 28295214 750 USB1 ARPublic db PMID: 29226301, 29226302 751 USP15 unknown Public db PMID:28295214 752 USP21 unknown Public db PMID: 28295214 753 USP25 unknownPublic db PMID: 28295214 754 USP3 unknown Public db PMID: 28295214 755VAV1 unknown Public db PMID: 29867916, 29921932 756 VDR AD AR Public dbPMID: 29867916 757 VEGFA association Public db PMID: 28681388 758 WASHC5AD AR Public db PMID: 29921932 759 WDR1 AR Public db PMID: 29226301,29226302 760 WRAP53 AR Public db PMID: 29226301, 29226302 761 XAF1unknown Public db PMID: 27381292, 28236279 762

TABLE 32 SEQ ID 2300-2893, transcript variants for Table 31 genes RefSeqGene RefSeq Accession Symbol Number mRNA Description SEQ ID ACD NM001082486 Homo sapiens adrenocortical dysplasia homolog (mouse) 2300(ACD), transcript variant 1, mRNA. ACD NM 001082487 Homo sapiensadrenocortical dysplasia homolog (mouse) 2301 (ACD), transcript variant3, mRNA. ACD NM 022914 Homo sapiens adrenocortical dysplasia homolog(mouse) 2302 (ACD), transcript variant 2, mRNA. ACTB NM 001101 Homosapiens actin, beta (ACTB), mRNA. 2303 ACTN4 NM 004924 Homo sapiensactinin, alpha 4 (ACTN4), mRNA. 2304 ADA2 NM 001282225.1 Homo sapiensadenosine deaminase 2, transcript variant 3 2305 ADA2 NM 001282226.1Homo sapiens adenosine deaminase 2, transcript variant 4 2306 ADA2 NM001282227.1 Homo sapiens adenosine deaminase 2, transcript variant 52307 ADA2 NM 001282228.1 Homo sapiens adenosine deaminase 2, transcriptvariant 6 2308 ADA2 NM 001282229.1 Homo sapiens adenosine deaminase 2,transcript variant 7 2309 ADA2 NM 177405.2 Homo sapiens adenosinedeaminase 2, transcript variant 2 2310 ADAM17 NM 003183 Homo sapiensADAM metallopeptidase domain 17 2311 (ADAM17), mRNA. ADGRL2 NM001297704.2 Homo sapiens adhesion G protein-coupled receptor L2, 2312transcript variant 2 ADGRL2 NM 001297705.2 Homo sapiens adhesion Gprotein-coupled receptor L2, 2313 transcript variant 3 ADGRL2 NM001297706.2 Homo sapiens adhesion G protein-coupled receptor L2, 2314transcript variant 4 ADGRL2 NM 001330645.2 Homo sapiens adhesion Gprotein-coupled receptor L2, 2315 transcript variant 5 ADGRL2 NM001350698.1 Homo sapiens adhesion G protein-coupled receptor L2, 2316transcript variant 6 ADGRL2 NM 001350699.1 Homo sapiens adhesion Gprotein-coupled receptor L2, 2317 transcript variant 7 ADGRL2 NM012302.4 Homo sapiens adhesion G protein-coupled receptor L2, 2318transcript variant 1 AIRE NM 000383 Homo sapiens autoimmune regulator(AIRE), mRNA. 2319 ANP32B NM 006401 Homo sapiens acidic (leucine-rich)nuclear phosphoprotein 2320 32 family, member B (ANP32B), mRNA. AP1S3 NM001039569 Homo sapiens adaptor-related protein complex 1, sigma 3 2321subunit (AP1S3), mRNA. ARPC1B NM 005720 Homo sapiens actin relatedprotein 2/3 complex, subunit 1B, 2322 41 kDa (ARPC1B), mRNA. ATG12 NM004707 Homo sapiens autophagy related 12 (ATG12), transcript 2323variant 1, mRNA. ATG12 NR 033362 Homo sapiens autophagy related 12(ATG12), transcript 2324 variant 2, non-coding RNA. ATG12 NR 033363 Homosapiens autophagy related 12 (ATG12), transcript 2325 variant 3,non-coding RNA. ATG12 NR 073603 Homo sapiens autophagy related 12(ATG12), transcript 2326 variant 4, non-coding RNA. ATG12 NR 073604 Homosapiens autophagy related 12 (ATG12), transcript 2327 variant 5,non-coding RNA. ATG12 NR 073605 Homo sapiens autophagy related 12(ATG12), transcript 2328 variant 5, non-coding RNA. ATG16L1 NM 001190266Homo sapiens autophagy related 16-like 1 (S. cerevisiae) 2329 (ATG16L1),transcript variant 4, mRNA. ATG16L1 NM 001190267 Homo sapiens autophagyrelated 16-like 1 (S. cerevisiae) 2330 (ATG16L1), transcript variant 5,mRNA. ATG16L1 NM 017974 Homo sapiens autophagy related 16-like 1 (S.cerevisiae) 2331 (ATG16L1), transcript variant 2, mRNA. ATG16L1 NM030803 Homo sapiens autophagy related 16-like 1 (S. cerevisiae) 2332(ATG16L1), transcript variant 1, mRNA. ATG16L1 NM 198890 Homo sapiensautophagy related 16-like 1 (S. cerevisiae) 2333 (ATG16L1), transcriptvariant 3, mRNA. ATG5 NM 004849 Homo sapiens autophagy related 5 (ATG5),mRNA. 2334 ATG7 NM 001136031 Homo sapiens autophagy related 7 (ATG7),transcript 2335 variant 2, mRNA. ATG7 NM 001144912 Homo sapiensautophagy related 7 (ATG7), transcript 2336 variant 3, mRNA. ATG7 NM006395 Homo sapiens autophagy related 7 (ATG7), transcript 2337 variant1, mRNA. ATG9A NM 001077198 Homo sapiens autophagy related 9A (ATG9A),transcript 2338 variant 1, mRNA. ATG9A NM 024085 Homo sapiens autophagyrelated 9A (ATG9A), transcript 2339 variant 2, mRNA. ATP6AP1 NM 001183Homo sapiens ATPase, H+ transporting, lysosomal 2340 accessory protein 1(ATP6AP1), mRNA. B2M NM 004048 Homo sapiens beta-2-microglobulin (B2M),mRNA. 2341 BCL11B NM 022898 Homo sapiens B-cell CLL/lymphoma 11B (zincfinger 2342 protein) (BCL11B), transcript variant 2, mRNA. BCL11B NM138576 Homo sapiens B-cell CLL/lymphoma 11B (zinc finger 2343 protein)(BCL11B), transcript variant 1, mRNA. BCL2 NM 000633 Homo sapiens B-cellCLL/lymphoma 2 (BCL2), transcript 2344 variant alpha, mRNA. BCL2 NM000657 Homo sapiens B-cell CLL/lymphoma 2 (BCL2), transcript 2345variant beta, mRNA. BLK NM 001715 Homo sapiens B lymphoid tyrosinekinase (BLK), mRNA. 2346 BRD4 NM 014299 Homo sapiens bromodomaincontaining 4 (BRD4), 2347 transcript variant short, mRNA. BRD4 NM 058243Homo sapiens bromodomain containing 4 (BRD4), 2348 transcript variantlong, mRNA. BTLA NM 001085357 Homo sapiens B and T lymphocyte associated(BTLA), 2349 transcript variant 2, mRNA. BTLA NM 181780 Homo sapiens Band T lymphocyte associated (BTLA), 2350 transcript variant 1, mRNA. C1RNM 001733 Homo sapiens complement component 1, r subcomponent 2351(C1R), mRNA. C1S NM 001734 Homo sapiens complement component 1, ssubcomponent 2352 (C1S), transcript variant 2, mRNA. C1S NM 201442 Homosapiens complement component 1, s subcomponent 2353 (C1S), transcriptvariant 1, mRNA. C2 NM 000063 Homo sapiens complement component 2 (C2),transcript 2354 variant 1, mRNA. C2 NM 001145903 Homo sapiens complementcomponent 2 (C2), transcript 2355 variant 2, mRNA. C2 NM 001178063 Homosapiens complement component 2 (C2), transcript 2356 variant 3, mRNA. C2NR 073063 Homo sapiens complement component 2 (C2), transcript 2357variant 4, non-coding RNA. C3 NM 000064 Homo sapiens complementcomponent 3 (C3), mRNA. 2358 C4A NM 001252204 Homo sapiens complementcomponent 4A (Rodgers blood 2359 group) (C4A), transcript variant 2,mRNA. C4A NM 007293 Homo sapiens complement component 4A (Rodgers blood2360 group) (C4A), transcript variant 1, mRNA. C4B NM 001002029 Homosapiens complement component 4B (Chido blood 2361 group) (C4B), mRNA. C5NM 001735 Homo sapiens complement component 5 (C5), mRNA. 2362 C6 NM000065 Homo sapiens complement component 6 (C6), transcript 2363 variant1, mRNA. C6 NM 001115131 Homo sapiens complement component 6 (C6),transcript 2364 variant 2, mRNA. C7 NM 000587 Homo sapiens complementcomponent 7 (C7), mRNA. 2365 C8A NM 000562 Homo sapiens complementcomponent 8, alpha polypeptide 2366 (C8A), mRNA. C8B NM 000066 Homosapiens complement component 8, beta polypeptide 2367 (C8B), transcriptvariant 1, mRNA. C8G NM 000606 Homo sapiens complement component 8,gamma 2368 polypeptide (C8G), mRNA. C9 NM 001737 Homo sapiens complementcomponent 9 (C9), mRNA. 2369 CAD NM 004341 Homo sapienscarbamoyl-phosphate synthetase 2, aspartate 2370 transcarbamylase, anddihydroorotase (CAD), mRNA. CAMLG NM 001745 Homo sapiens calciummodulating ligand (CAMLG), 2371 mRNA. CARD14 NM 001257970 Homo sapienscaspase recruitment domain family, member 2372 14 (CARD14), transcriptvariant 3, mRNA. CARD14 NM 024110 Homo sapiens caspase recruitmentdomain family, member 2373 14 (CARD14), transcript variant 1, mRNA.CARD14 NM 052819 Homo sapiens caspase recruitment domain family, member2374 14 (CARD14), transcript variant 2, mRNA. CARD14 NR 047566 Homosapiens caspase recruitment domain family, member 2375 14 (CARD14),transcript variant 4, non-coding RNA. CASP10 NM 001206524 Homo sapienscaspase 10, apoptosis-related cysteine 2376 peptidase (CASP10),transcript variant 6, mRNA. CASP10 NM 001206542 Homo sapiens caspase 10,apoptosis-related cysteine 2377 peptidase (CASP10), transcript variant5, mRNA. CASP10 NM 001230 Homo sapiens caspase 10, apoptosis-relatedcysteine 2378 peptidase (CASP10), transcript variant 3, mRNA. CASP10 NM032974 Homo sapiens caspase 10, apoptosis-related cysteine 2379peptidase (CASP10), transcript variant 2, mRNA. CASP10 NM 032976 Homosapiens caspase 10, apoptosis-related cysteine 2380 peptidase (CASP10),transcript variant 4, mRNA. CASP10 NM 032977 Homo sapiens caspase 10,apoptosis-related cysteine 2381 peptidase (CASP10), transcript variant1, mRNA. CAV1 NM 001172895 Homo sapiens caveolin 1, caveolae protein, 22kDa (CAV1), 2382 transcript variant 2, mRNA. CAV1 NM 001172896 Homosapiens caveolin 1, caveolae protein, 22 kDa (CAV1), 2383 transcriptvariant 3, mRNA. CAV1 NM 001172897 Homo sapiens caveolin 1, caveolaeprotein, 22 kDa (CAV1), 2384 transcript variant 4, mRNA. CAV1 NM 001753Homo sapiens caveolin 1, caveolae protein, 22 kDa (CAV1), 2385transcript variant 1. mRNA. CCBE1 NM 133459 Homo sapiens collagen andcalcium binding EGF domains 1 2386 (CCBE1), mRNA. CCDC22 NM 014008 Homosapiens coiled-coil domain containing 22 (CCDC22), 2387 mRNA. CCZ1 NM015622 Homo sapiens CCZ1 vacuolar protein trafficking and 2388biogenesis associated homolog (S. cerevisiae) (CCZ1), mRNA. CD22 NM001185099 Homo sapiens CD22 molecule (CD22), transcript variant 2, 2389mRNA. CD22 NM 001185100 Homo sapiens CD22 molecule (CD22), transcriptvariant 3, 2390 mRNA. CD22 NM 001185101 Homo sapiens CD22 molecule(CD22), transcript variant 4, 2391 mRNA. CD22 NM 001771 Homo sapiensCD22 molecule (CD22), transcript variant 1, 2392 mRNA. CD274 NM001267706 Homo sapiens CD274 molecule (CD274), transcript variant 23932, mRNA. CD274 NM 014143 Homo sapiens CD274 molecule (CD274), transcriptvariant 2394 1, mRNA. CD274 NR 052005 Homo sapiens CD274 molecule(CD274), transcript variant 2395 3, non-coding RNA. CD276 NM 001024736Homo sapiens CD276 molecule (CD276), transcript variant 2396 1, mRNA.CD276 NM 025240 Homo sapiens CD276 molecule (CD276), transcript variant2397 2, mRNA. CD36 NM 000072 Homo sapiens CD36 molecule (thrombospondinreceptor) 2398 (CD36), transcript variant 3, mRNA. CD36 NM 001001547Homo sapiens CD36 molecule (thrombospondin receptor) 2399 (CD36),transcript variant 2, mRNA. CD36 NM 001001548 Homo sapiens CD36 molecule(thrombospondin receptor) 2400 (CD36), transcript variant 1, mRNA. CD36NM 001127443 Homo sapiens CD36 molecule (thrombospondin receptor) 2401(CD36), transcript variant 4, mRNA. CD36 NM 001127444 Homo sapiens CD36molecule (thrombospondin receptor) 2402 (CD36), transcript variant 5,mRNA. CD37 NM 001040031 Homo sapiens CD37 molecule (CD37), transcriptvariant 2, 2403 mRNA. CD37 NM 001774 Homo sapiens CD37 molecule (CD37),transcript variant 1, 2404 mRNA. CD38 NM 001775 Homo sapiens CD38molecule (CD38), mRNA. 2405 CD46 NM 002389 Homo sapiens CD46 molecule,complement regulatory 2406 protein (CD46), transcript variant a, mRNA.CD46 NM 153826 Homo sapiens CD46 molecule, complement regulatory 2407protein (CD46), transcript variant d, mRNA. CD46 NM 172350 Homo sapiensCD46 molecule, complement regulatory 2408 protein (CD46), transcriptvariant n, mRNA. CD46 NM 172351 Homo sapiens CD46 molecule, complementregulatory 2409 protein (CD46), transcript variant c, mRNA. CD46 NM172352 Homo sapiens CD46 molecule, complement regulatory 2410 protein(CD46), transcript variant e, mRNA. CD46 NM 172353 Homo sapiens CD46molecule, complement regulatory 2411 protein (CD46), transcript variantf, mRNA. CD46 NM 172359 Homo sapiens CD46 molecule, complementregulatory 2412 protein (CD46), transcript variant b, mRNA. CD46 NM172361 Homo sapiens CD46 molecule, complement regulatory 2413 protein(CD46), transcript variant 1, mRNA. CD5 NM 014207 Homo sapiens CD5molecule (CD5), mRNA. 2414 CD70 NM 001252 Homo sapiens CD70 molecule(CD70), mRNA. 2415 CD72 NM 001782 Homo sapiens CD72 molecule (CD72),mRNA. 2416 CD74 NM 001025158 Homo sapiens CD74 molecule, majorhistocompatibility 2417 complex, class II invariant chain (CD74),transcript variant 3, mRNA. CD74 NM 001025159 Homo sapiens CD74molecule, major histocompatibility 2418 complex, class II invariantchain (CD74), transcript variant 1, mRNA. CD74 NM 004355 Homo sapiensCD74 molecule, major histocompatibility 2419 complex, class II invariantchain (CD74), transcript variant 2, mRNA. CD84 NM 001184879 Homo sapiensCD84 molecule (CD84), transcript variant 1, 2420 mRNA. CD84 NM 001184881Homo sapiens CD84 molecule (CD84), transcript variant 3, 2421 mRNA. CD84NM 001184882 Homo sapiens CD84 molecule (CD84), transcript variant 4,2422 mRNA. CD84 NM 003874 Homo sapiens CD84 molecule (CD84), transcriptvariant 2, 2423 mRNA. CD93 NM 012072 Homo sapiens CD93 molecule (CD93),mRNA. 2424 CEBPE NM 001805 Homo sapiens CCAAT/enhancer binding protein(C/EBP), 2425 epsilon (CEBPE), mRNA. CFB NM 001710 Homo sapienscomplement factor B (CFB), mRNA. 2426 CFD NM 001928 Homo sapienscomplement factor D (adipsin) (CFD), 2427 mRNA. CFH NM 000186 Homosapiens complement factor H (CFH), transcript 2428 variant 1, mRNA. CFHNM 001014975 Homo sapiens complement factor H (CFH), transcript 2429variant 2, mRNA. CFHR1 NM 002113 Homo sapiens complement factorH-related 1 (CFHR1), 2430 mRNA. CFHR2 NM 005666 Homo sapiens complementfactor H-related 2 (CFHR2), 2431 mRNA. CFHR3 NM 001166624 Homo sapienscomplement factor H-related 3 (CFHR3), 2432 transcript variant 2, mRNA.CFHR3 NM 021023 Homo sapiens complement factor H-related 3 (CFHR3), 2433transcript variant 1, mRNA. CFHR4 NM 001201550 Homo sapiens complementfactor H-related 4 (CFHR4), 2434 transcript variant 1, mRNA. CFHR4 NM001201551 Homo sapiens complement factor H-related 4 (CFHR4), 2435transcript variant 2, mRNA. CFHR4 NM 006684 Homo sapiens complementfactor H-related 4 (CFHR4), 2436 transcript variant 3, mRNA. CFHR5 NM030787 Homo sapiens complement factor H-related 5 (CFHR5), 2437 mRNA.CFI NM 000204 Homo sapiens complement factor I (CFI), mRNA. 2438 CFP NM001145252 Homo sapiens complement factor properdin (CFP), 2439transcript variant 2, mRNA. CFP NM 002621 Homo sapiens complement factorproperdin (CFP), 2440 transcript variant 1, mRNA. CFTR NM 000492 Homosapiens cystic fibrosis transmembrane conductance 2441 regulator(ATP-binding cassette sub-family C, member 7) (CFTR), mRNA. CHD2 NM001042572 Homo sapiens chromodomain helicase DNA binding protein 2442 2(CHD2), transcript variant 2, mRNA. CHD2 NM 001271 Homo sapienschromodomain helicase DNA binding protein 2443 2 (CHD2), transcriptvariant 1, mRNA. CLEC16A NM 001243403 Homo sapiens C-type lectin domainfamily 16, member A 2444 (CLEC16A), transcript variant 2, mRNA. CLEC16ANM 015226 Homo sapiens C-type lectin domain family 16, member A 2445(CLEC16A), transcript variant 1, mRNA. CLPB NM 001258392 Homo sapiensClpB caseinolytic peptidase B homolog (E. 2446 coli) (CLPB), transcriptvariant 2, mRNA. CLPB NM 001258393 Homo sapiens ClpB caseinolyticpeptidase B homolog (E. 2447 coli) (CLPB), transcript variant 3, mRNA.CLPB NM 001258394 Homo sapiens ClpB caseinolytic peptidase B homolog (E.2448 coli) (CLPB), transcript variant 4, mRNA. CLPB NM 030813 Homosapiens ClpB caseinolytic peptidase B homolog (E. 2449 coli) (CLPB),transcript variant 1, mRNA. COPA NM 001098398 Homo sapiens coatomerprotein complex, subunit alpha 2450 (COPA), transcript variant 1, mRNA.COPA NM 004371 Homo sapiens coatomer protein complex, subunit alpha 2451(COPA), transcript variant 2, mRNA. CSF2RA NM 001161529 Homo sapienscolony stimulating factor 2 receptor, alpha, 2452 low-affinity(granulocyte-macrophage) (CSF2RA), transcript variant 7, mRNA. CSF2RA NM001161530 Homo sapiens colony stimulating factor 2 receptor, alpha, 2453low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 8,mRNA. CSF2RA NM 001161531 Homo sapiens colony stimulating factor 2receptor, alpha, 2454 low-affinity (granulocyte-macrophage) (CSF2RA),transcript variant 9, mRNA. CSF2RA NM 001161532 Homo sapiens colonystimulating factor 2 receptor, alpha, 2455 low-affinity(granulocyte-macrophage) (CSF2RA), transcript variant 10, mRNA. CSF2RANM 006140 Homo sapiens colony stimulating factor 2 receptor, alpha, 2456low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 1,mRNA. CSF2RA NM 172245 Homo sapiens colony stimulating factor 2receptor, alpha, 2457 low-affinity (granulocyte-macrophage) (CSF2RA),transcript variant 2, mRNA. CSF2RA NM 172246 Homo sapiens colonystimulating factor 2 receptor, alpha, 2458 low-affinity(granulocyte-macrophage) (CSF2RA), transcript variant 3, mRNA. CSF2RA NM172247 Homo sapiens colony stimulating factor 2 receptor, alpha, 2459low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 4,mRNA. CSF2RA NM 172249 Homo sapiens colony stimulating factor 2receptor, alpha, 2460 low-affinity (granulocyte-macrophage) (CSF2RA),transcript variant 6, mRNA. CSF2RA NR 027760 Homo sapiens colonystimulating factor 2 receptor, alpha, 2461 low-affinity(granulocyte-macrophage) (CSF2RA), transcript variant 11, non-codingRNA. CSF2RB NM 000395 Homo sapiens colony stimulating factor 2 receptor,beta, 2462 low-affinity (granulocyte-macrophage) (CSF2RB), mRNA. CTC1 NM025099 Homo sapiens CTS telomere maintenance complex 2463 component 1(CTC1), transcript variant 1, mRNA. CTC1 NR 046431 Homo sapiens CTStelomere maintenance complex 2464 component 1 (CTC1), transcript variant2, non-coding RNA. CXCL1 NM 001511 Homo sapiens chemokine (C-X-C motif)ligand 1 2465 (melanoma growth stimulating activity, alpha) (CXCL1),transcript variant 1, mRNA. CXCL1 NR 046035 Homo sapiens chemokine(C-X-C motif) ligand 1 2466 (melanoma growth stimulating activity,alpha) (CXCL1), transcript variant 2, non-coding RNA. CXCL10 NM 001565Homo sapiens chemokine (C-X-C motif) ligand 10 2467 (CXCL10), mRNA.CXCL5 NM 002994 Homo sapiens chemokine (C-X-C motif) ligand 5 (CXCL5),2468 mRNA. CXCL8 NM 000584.3 Homo sapiens C-X-C motif chemokine ligand8, transcript 2469 variant 1 CXCL8 NM 001354840.1 Homo sapiens C-X-Cmotif chemokine ligand 8, transcript 2470 variant 2 CXCR3 NM 001142797Homo sapiens chemokine (C-X-C motif) receptor 3 2471 (CXCR3), transcriptvariant 2, mRNA. CXCR3 NM 001504 Homo sapiens chemokine (C-X-C motif)receptor 3 2472 (CXCR3), transcript variant 1, mRNA. CYBA NM 000101 Homosapiens cytochrome b-245, alpha polypeptide 2473 (CYBA), mRNA. DCLRE1BNM 022836 Homo sapiens DNA cross-link repair 1B (DCLRE1B), 2474 mRNA.DNAJC21 NM 001012339 Homo sapiens DnaJ (Hsp40) homolog, subfamily C,2475 member 21 (DNAJC21), transcript variant 2, mRNA. DNAJC21 NM 194283Homo sapiens DnaJ (Hsp40) homolog, subfamily C, 2476 member 21(DNAJC21), transcript variant 1, mRNA. DNASE1L3 NM 001256560 Homosapiens deoxyribonuclease I-like 3 (DNASE1L3), 2477 transcript variant2, mRNA. DNASE1L3 NM 004944 Homo sapiens deoxyribonuclease I-like 3(DNASE1L3), 2478 transcript variant 1, mRNA. DNASE2 NM 001375 Homosapiens deoxyribonuclease II, lysosomal (DNASE2), 2479 mRNA. EBF1 NM024007 Homo sapiens early B-cell factor 1 (EBF1), mRNA. 2480 EGF NM001178130 Homo sapiens epidermal growth factor (EGF), transcript 2481variant 2, mRNA. EGF NM 001178131 Homo sapiens epidermal growth factor(EGF), transcript 2482 variant 3, mRNA. EGF NM 001963 Homo sapiensepidermal growth factor (EGF), transcript 2483 variant 1, mRNA. ERCC6L2NM 001010895 Homo sapiens excision repair cross-complementing rodent2484 repair deficiency, complementation group 6-like 2 (ERCC6L2), mRNA.EXTL3 NM 001440 Homo sapiens exostosin-like glycosyltransferase 3 2485(EXTL3), transcript variant 1, mRNA. EXTL3 NR 073468 Homo sapiensexostosin-like glycosyltransferase 3 2486 (EXTL3), transcript variant 2,non-coding RNA. EXTL3 NR 073469 Homo sapiens exostosin-likeglycosyltransferase 3 2487 (EXTL3), transcript variant 3, non-codingRNA. FAAP24 NM 001300978.1 Homo sapiens Fanconi anemia core complexassociated 2488 protein 24, transcript variant 2 FAAP24 NM 152266.4 Homosapiens Fanconi anemia core complex associated 2489 protein 24,transcript variant 1 FADD NM 003824 Homo sapiens Fas(TNFRSF6)-associated via death domain 2490 (FADD), mRNA. FAT4 NM 024582Homo sapiens FAT atypical cadherin 4 (FAT4), mRNA. 2491 FCER2 NM001207019 Homo sapiens Fc fragment of IgE, low affinity II, receptor2492 for (CD23) (FCER2), transcript variant 2, mRNA. FCER2 NM 001220500Homo sapiens Fc fragment of IgE, low affinity II, receptor 2493 for(CD23) (FCER2), transcript variant 3, mRNA. FCER2 NM 002002 Homo sapiensFc fragment of IgE, low affinity II, receptor 2494 for (CD23) (FCER2),transcript variant 1, mRNA. FERMT3 NM 031471 Homo sapiens fermitinfamily member 3 (FERMT3), 2495 transcript variant URP2SF, mRNA. FERMT3NM 178443 Homo sapiens fermitin family member 3 (FERMT3), 2496transcript variant URP2LF, mRNA. FIS1 NM 016068 Homo sapiens fission 1(mitochondrial outer membrane) 2497 homolog (S. cerevisiae) (FIS1),mRNA. G6PD NM 000402 Homo sapiens glucose-6-phosphate dehydrogenase(G6PD), 2498 transcript variant 1, mRNA. G6PD NM 001042351 Homo sapiensglucose-6-phosphate dehydrogenase (G6PD), 2499 transcript variant 2,mRNA. GINS1 NM 021067 Homo sapiens GINS complex subunit 1 (Psf1 homolog)2500 (GINS1), mRNA. HERC5 NM 016323 Homo sapiens HECT and RLD domaincontaining E3 2501 ubiquitin protein ligase 5 (HERC5), mRNA. HERC6 NM001165136 Homo sapiens HECT and RLD domain containing E3 2502 ubiquitinprotein ligase family member 6 (HERC6), transcript variant 2, mRNA.HERC6 NM 017912 Homo sapiens HECT and RLD domain containing E3 2503ubiquitin protein ligase family member 6 (HERC6), transcript variant 1,mRNA. HMGB1 NM 002128 Homo sapiens high mobility group box 1 (HMGB1),2504 mRNA. HMOX1 NM 002133 Homo sapiens heme oxygenase (decycling) 1(HMOX1), 2505 mRNA. HYOU1 NM 001130991 Homo sapiens hypoxia up-regulated1 (HYOU1), transcript 2506 variant 2, mRNA. HYOU1 NM 006389 Homo sapienshypoxia up-regulated 1 (HYOU1), transcript 2507 variant 1, mRNA. ICAM1NM 000201 Homo sapiens intercellular adhesion molecule 1 (ICAM1), 2508mRNA. ICOSLG NM 015259 Homo sapiens inducible T-cell co-stimulatorligand 2509 (ICOSLG), mRNA. IFI35 NM 005533 Homo sapiensinterferon-induced protein 35 (IFI35), 2510 mRNA. IFIT1 NM 001270927Homo sapiens interferon-induced protein with 2511 tetratricopeptiderepeats 1 (IFIT1), transcript variant 2, mRNA. IFIT1 NM 001270928 Homosapiens interferon-induced protein with 2512 tetratricopeptide repeats 1(IFIT1), transcript variant 3, mRNA. IFIT1 NM 001270929 Homo sapiensinterferon-induced protein with 2513 tetratricopeptide repeats 1(IFIT1), transcript variant 4, mRNA. IFIT1 NM 001270930 Homo sapiensinterferon-induced protein with 2514 tetratricopeptide repeats 1(IFIT1), transcript variant 5, mRNA. IFIT1 NM 001548 Homo sapiensinterferon-induced protein with 2515 tetratricopeptide repeats 1(IFIT1), transcript variant 1, mRNA. IFIT2 NM 001547 Homo sapiensinterferon-induced protein with 2516 tetratricopeptide repeats 2(IFIT2), mRNA. IFIT3 NM 001031683 Homo sapiens interferon-inducedprotein with 2517 tetratricopeptide repeats 3 (IFIT3), transcriptvariant 2, mRNA. IFIT3 NM 001549 Homo sapiens interferon-induced proteinwith 2518 tetratricopeptide repeats 3 (IFIT3), transcript variant 1,mRNA. IGHMBP2 NM 002180 Homo sapiens immunoglobulin mu binding protein 22519 (IGHMBP2), mRNA. IL17RC NM 001203263 Homo sapiens interleukin 17receptor C (IL17RC), transcript 2520 variant 4, mRNA. IL17RC NM001203264 Homo sapiens interleukin 17 receptor C (IL17RC), transcript2521 variant 5, mRNA. IL17RC NM 001203265 Homo sapiens interleukin 17receptor C (IL17RC), transcript 2522 variant 6, mRNA. IL17RC NM 032732Homo sapiens interleukin 17 receptor C (IL17RC), transcript 2523 variant3, mRNA. IL17RC NM 153460 Homo sapiens interleukin 17 receptor C(IL17RC), transcript 2524 variant 1, mRNA. IL17RC NM 153461 Homo sapiensinterleukin 17 receptor C (IL17RC), transcript 2525 variant 2, mRNA.IL17RC NR 037807 Homo sapiens interleukin 17 receptor C (IL17RC),transcript 2526 variant 7, non-coding RNA. IL1RN NM 000577 Homo sapiensinterleukin 1 receptor antagonist (IL1RN), 2527 transcript variant 3,mRNA. IL1RN NM 173841 Homo sapiens interleukin 1 receptor antagonist(IL1RN), 2528 transcript variant 2, mRNA. IL1RN NM 173842 Homo sapiensinterleukin 1 receptor antagonist (IL1RN), 2529 transcript variant 1,mRNA. IL1RN NM 173843 Homo sapiens interleukin 1 receptor antagonist(IL1RN), 2530 transcript variant 4, mRNA. IL3 NM 000588 Homo sapiensinterleukin 3 (colony-stimulating factor, 2531 multiple) (IL3), mRNA.IL36RN NM 012275 Homo sapiens interleukin 36 receptor antagonist(IL36RN), 2532 transcript variant 1, mRNA. IL36RN NM 173170 Homo sapiensinterleukin 36 receptor antagonist (IL36RN), 2533 transcript variant 2,mRNA. IL4 NM 000589 Homo sapiens interleukin 4 (IL4), transcript variant1, 2534 mRNA. IL4 NM 172348 Homo sapiens interleukin 4 (IL4), transcriptvariant 2, 2535 mRNA. INO80 NM 017553 Homo sapiens INO80 complex subunit(INO80), transcript 2536 variant 1, mRNA. INPP5D NM 001017915 Homosapiens inositol polyphosphate-5-phosphatase, 2537 145 kDa (INPP5D),transcript variant 1, mRNA. INPP5D NM 005541 Homo sapiens inositolpolyphosphate-5-phosphatase, 2538 145 kDa (INPP5D), transcript variant2, mRNA. IRAK1 NM 001025242 Homo sapiens interleukin-1receptor-associated kinase 1 2539 (IRAK1), transcript variant 2, mRNA.IRAK1 NM 001025243 Homo sapiens interleukin-1 receptor-associated kinase1 2540 (IRAK1), transcript variant 3, mRNA. IRAK1 NM 001569 Homo sapiensinterleukin-1 receptor-associated kinase 1 2541 (IRAK1), transcriptvariant 1, mRNA. IRF2BP2 NM 001077397 Homo sapiens interferon regulatoryfactor 2 binding protein 2542 2 (IRF2BP2), transcript variant 2, mRNA.IRF2BP2 NM 182972 Homo sapiens interferon regulatory factor 2 bindingprotein 2543 2 (IRF2BP2), transcript variant 1, mRNA. ITCH NM 001257137Homo sapiens itchy E3 ubiquitin protein ligase (ITCH), 2544 transcriptvariant 1, mRNA. ITCH NM 001257138 Homo sapiens itchy E3 ubiquitinprotein ligase (ITCH), 2545 transcript variant 3, mRNA. ITCH NM 031483Homo sapiens itchy E3 ubiquitin protein ligase (ITCH), 2546 transcriptvariant 2, mRNA. ITGAM NM 000632 Homo sapiens integrin, alpha M(complement component 3 2547 receptor 3 subunit) (ITGAM), transcriptvariant 2, mRNA. ITGAM NM 001145808 Homo sapiens integrin, alpha M(complement component 3 2548 receptor 3 subunit) (ITGAM), transcriptvariant 1, mRNA. ITGB2 NM 000211 Homo sapiens integrin, beta 2(complement component 3 2549 receptor 3 and 4 subunit) (ITGB2),transcript variant 1, mRNA. ITGB2 NM 001127491 Homo sapiens integrin,beta 2 (complement component 3 2550 receptor 3 and 4 subunit) (ITGB2),transcript variant 2, mRNA. ITPKB NM 002221 Homo sapiensinositol-trisphosphate 3-kinase B (ITPKB), 2551 mRNA. ITSN1 NM 001001132Homo sapiens intersectin 1 (SH3 domain protein) (ITSN1), 2552 transcriptvariant 2, mRNA. ITSN1 NM 003024 Homo sapiens intersectin 1 (SH3 domainprotein) (ITSN1), 2553 transcript variant 1, mRNA. JAK1 NM 002227 Homosapiens Janus kinase 1 (JAK1), mRNA. 2554 KDM6A NM 021140 Homo sapienslysine (K)-specific demethylase 6A 2555 (KDM6A), mRNA. KMT2D NM 003482Homo sapiens lysine (K)-specific methyltransferase 2D 2556 (KMT2D),mRNA. KRAS NM 004985 Homo sapiens Kirsten rat sarcoma viral oncogenehomolog 2557 (KRAS), transcript variant b, mRNA. KRAS NM 033360 Homosapiens Kirsten rat sarcoma viral oncogene homolog 2558 (KRAS),transcript variant a, mRNA. LAT NM 001014987 Homo sapiens linker foractivation of T cells (LAT), 2559 transcript variant 2, mRNA. LAT NM001014988 Homo sapiens linker for activation of T cells (LAT), 2560transcript variant 3, mRNA. LAT NM 001014989 Homo sapiens linker foractivation of T cells (LAT), 2561 transcript variant 4, mRNA. LAT NM014387 Homo sapiens linker for activation of T cells (LAT), 2562transcript variant 1, mRNA. LPIN2 NM 014646 Homo sapiens lipin 2(LPIN2), mRNA. 2563 LRRK2 NM 198578 Homo sapiens leucine-rich repeatkinase 2 (LRRK2), 2564 mRNA. MAP3K14 NM 003954 Homo sapiensmitogen-activated protein kinase kinase 2565 kinase 14 (MAP3K14), mRNA.MASP2 NM 006610 Homo sapiens mannan-binding lectin serine peptidase 22566 (MASP2), transcript variant 1, mRNA. MASP2 NM 139208 Homo sapiensmannan-binding lectin serine peptidase 2 2567 (MASP2), transcriptvariant 2, mRNA. MB21D1 NM 138441 Homo sapiens Mab-21 domain containing1 (MB21D1), 2568 mRNA. MBL2 NM 000242 Homo sapiens mannose-bindinglectin (protein C) 2, soluble 2569 (MBL2), mRNA. MCM4 NM 005914 Homosapiens minichromosome maintenance complex 2570 component 4 (MCM4),transcript variant 1, mRNA. MCM4 NM 182746 Homo sapiens minichromosomemaintenance complex 2571 component 4 (MCM4), transcript variant 2, mRNA.MCM5 NM 006739 Homo sapiens minichromosome maintenance complex 2572component 5 (MCM5), mRNA. MDC1 NM 014641 Homo sapiens mediator ofDNA-damage checkpoint 1 2573 (MDC1), mRNA. MEF2C NM 001131005 Homosapiens myocyte enhancer factor 2C (MEF2C), 2574 transcript variant 2,mRNA. MEF2C NM 001193347 Homo sapiens myocyte enhancer factor 2C(MEF2C), 2575 transcript variant 3, mRNA. MEF2C NM 001193348 Homosapiens myocyte enhancer factor 2C (MEF2C), 2576 transcript variant 4,mRNA. MEF2C NM 001193349 Homo sapiens myocyte enhancer factor 2C(MEF2C), 2577 transcript variant 5, mRNA. MEF2C NM 001193350 Homosapiens myocyte enhancer factor 2C (MEF2C), 2578 transcript variant 6,mRNA. MEF2C NM 002397 Homo sapiens myocyte enhancer factor 2C (MEF2C),2579 transcript variant 1, mRNA. MEFV NM 000243 Homo sapiensMediterranean fever (MEFV), transcript 2580 variant 1, mRNA. MEFV NM001198536 Homo sapiens Mediterranean fever (MEFV), transcript 2581variant 2, mRNA. MFN1 NM 033540 Homo sapiens mitofusin 1 (MFN1), mRNA.2582 MFN2 NM 001127660 Homo sapiens mitofusin 2 (MFN2), transcriptvariant 2, 2583 mRNA. MFN2 NM 014874 Homo sapiens mitofusin 2 (MFN2),transcript variant 1, 2584 mRNA. MLH1 NM 000249 Homo sapiens mutLhomolog 1, colon cancer, nonpolyposis 2585 type 2 (E. coli) (MLH1),transcript variant 1, mRNA. MLH1 NM 001167617 Homo sapiens mutL homolog1, colon cancer, nonpolyposis 2586 type 2 (E. coli) (MLH1), transcriptvariant 2, mRNA. MLH1 NM 001167618 Homo sapiens mutL homolog 1, coloncancer, nonpolyposis 2587 type 2 (E. coli) (MLH1), transcript variant 3,mRNA. MLH1 NM 001167619 Homo sapiens mutL homolog 1, colon cancer,nonpolyposis 2588 type 2 (E. coli) (MLH1), transcript variant 4, mRNA.MLH1 NM 001258271 Homo sapiens mutL homolog 1, colon cancer,nonpolyposis 2589 type 2 (E. coli) (MLH1), transcript variant 5, mRNA.MLH1 NM 001258273 Homo sapiens mutL homolog 1, colon cancer,nonpolyposis 2590 type 2 (E. coli) (MLH1), transcript variant 6, mRNA.MLH1 NM 001258274 Homo sapiens mutL homolog 1, colon cancer,nonpolyposis 2591 type 2 (E. coli) (MLH1), transcript variant 7, mRNA.MMP9 NM 004994 Homo sapiens matrix metallopeptidase 9 (gelatinase B,2592 92 kDa gelatinase, 92 kDa type IV collagenase) (MMP9), mRNA. MOGSNM 001146158 Homo sapiens mannosyl-oligosaccharide glucosidase 2593(MOGS), transcript variant 2, mRNA. MOGS NM 006302 Homo sapiensmannosyl-oligosaccharide glucosidase 2594 (MOGS), transcript variant 1,mRNA. MON1A NM 001142501 Homo sapiens MON1 secretory trafficking familymember 2595 A (MON1A), transcript variant 2, mRNA. MON1A NM 032355 Homosapiens MON1 secretory trafficking family member 2596 A (MON1A),transcript variant 1, mRNA. MON1B NM 014940 Homo sapiens MON1 secretorytrafficking family member 2597 B (MON1B), mRNA. MSH2 NM 000251 Homosapiens mutS homolog 2, colon cancer, nonpolyposis 2598 type 1 (E. coli)(MSH2), transcript variant 1, mRNA. MSH2 NM 001258281 Homo sapiens mutShomolog 2, colon cancer, nonpolyposis 2599 type 1 (E. coli) (MSH2),transcript variant 2, mRNA. MSH5 NM 002441 Homo sapiens mutS homolog 5(E. coli) (MSH5), transcript 2600 variant 3, mRNA. MSH5 NM 025259 Homosapiens mutS homolog 5 (E. coli) (MSH5), transcript 2601 variant 1,mRNA. MSH5 NM 172165 Homo sapiens mutS homolog 5 (E. coli) (MSH5),transcript 2602 variant 2, mRNA. MSH5 NM 172166 Homo sapiens mutShomolog 5 (E. coli) (MSH5), transcript 2603 variant 4, mRNA. MSH6 NM000179 Homo sapiens mutS homolog 6 (E. coli) (MSH6), transcript 2604variant 1, mRNA. MVK NM 000431 Homo sapiens mevalonate kinase (MVK),transcript variant 2605 1, mRNA. MVK NM 001114185 Homo sapiensmevalonate kinase (MVK), transcript variant 2606 2, mRNA. MX1 NM001144925 Homo sapiens myxovirus (influenza virus) resistance 1, 2607interferon-inducible protein p78 (mouse) (MX1), transcript variant 1,mRNA. MX1 NM 001178046 Homo sapiens myxovirus (influenza virus)resistance 1, 2608 interferon-inducible protein p78 (mouse) (MX1),transcript variant 3, mRNA. MX1 NM 002462 Homo sapiens myxovirus(influenza virus) resistance 1, 2609 interferon-inducible protein p78(mouse) (MX1), transcript variant 2, mRNA. MX2 NM 002463 Homo sapiensmyxovirus (influenza virus) resistance 2 2610 (mouse) (MX2), mRNA. MYSM1NM 001085487 Homo sapiens Myb-like, SWIRM and MPN domains 1 2611(MYSM1), mRNA. NBAS NM 015909 Homo sapiens neuroblastoma amplifiedsequence (NBAS), 2612 transcript variant 1, mRNA. NBAS NR 052013 Homosapiens neuroblastoma amplified sequence (NBAS), 2613 transcript variant2, non-coding RNA. NCF1 NM 000265 Homo sapiens neutrophil cytosolicfactor 1 (NCF1), mRNA. 2614 NCF2 NM 000433 Homo sapiens neutrophilcytosolic factor 2 (NCF2), 2615 transcript variant 1, mRNA. NCF2 NM001127651 Homo sapiens neutrophil cytosolic factor 2 (NCF2), 2616transcript variant 2, mRNA. NCF2 NM 001190789 Homo sapiens neutrophilcytosolic factor 2 (NCF2). 2617 transcript variant 4, mRNA. NCF2 NM001190794 Homo sapiens neutrophil cytosolic factor 2 (NCF2), 2618transcript variant 3, mRNA. NCF4 NM 000631 Homo sapiens neutrophilcytosolic factor 4, 40 kDa (NCF4), 2619 transcript variant 1, mRNA. NCF4NM 013416 Homo sapiens neutrophil cytosolic factor 4, 40 kDa (NCF4),2620 transcript variant 2, mRNA. NCSTN NM 015331 Homo sapiens nicastrin(NCSTN), mRNA. 2621 NFAT5 NM 001113178 Homo sapiens nuclear factor ofactivated T-cells 5, tonicity- 2622 responsive (NFAT5), transcriptvariant 6, mRNA. NFAT5 NM 006599 Homo sapiens nuclear factor ofactivated T-cells 5, tonicity- 2623 responsive (NFAT5), transcriptvariant 3, mRNA. NFAT5 NM 138713 Homo sapiens nuclear factor ofactivated T-cells 5, tonicity- 2624 responsive (NFAT5), transcriptvariant 2, mRNA. NFAT5 NM 138714 Homo sapiens nuclear factor ofactivated T-cells 5, tonicity- 2625 responsive (NFAT5), transcriptvariant 1, mRNA. NFAT5 NM 173214 Homo sapiens nuclear factor ofactivated T-cells 5, tonicity- 2626 responsive (NFAT5), transcriptvariant 4, mRNA. NFAT5 NM 173215 Homo sapiens nuclear factor ofactivated T-cells 5, tonicity- 2627 responsive (NFAT5), transcriptvariant 5, mRNA. NHP2 NM 001034833 Homo sapiens NHP2 ribonucleoprotein(NHP2), transcript 2628 variant 2, mRNA. NHP2 NM 017838 Homo sapiensNHP2 ribonucleoprotein (NHP2), transcript 2629 variant 1, mRNA. NLRC4 NM001199138 Homo sapiens NLR family, CARD domain containing 4 2630(NLRC4), transcript variant 2, mRNA. NLRC4 NM 001199139 Homo sapiens NLRfamily, CARD domain containing 4 2631 (NLRC4), transcript variant 3,mRNA. NLRC4 NM 021209 Homo sapiens NLR family, CARD domain containing 42632 (NLRC4), transcript variant 1, mRNA. NLRP1 NM 001033053 Homosapiens NLR family, pyrin domain containing 1 2633 (NLRP1), transcriptvariant 5, mRNA. NLRP1 NM 014922 Homo sapiens NLR family, pyrin domaincontaining 1 2634 (NLRP1), transcript variant 2, mRNA. NLRP1 NM 033004Homo sapiens NLR family, pyrin domain containing 1 2635 (NLRP1),transcript variant 1, mRNA. NLRP1 NM 033006 Homo sapiens NLR family,pyrin domain containing 1 2636 (NLRP1), transcript variant 3, mRNA.NLRP1 NM 033007 Homo sapiens NLR family, pyrin domain containing 1 2637(NLRP1), transcript variant 4, mRNA. NLRP2 NM 001174081 Homo sapiens NLRfamily, pyrin domain containing 2 2638 (NLRP2), transcript variant 2,mRNA. NLRP2 NM 001174082 Homo sapiens NLR family, pyrin domaincontaining 2 2639 (NLRP2), transcript variant 3, mRNA. NLRP2 NM001174083 Homo sapiens NLR family, pyrin domain containing 2 2640(NLRP2), transcript variant 4, mRNA. NLRP2 NM 017852 Homo sapiens NLRfamily, pyrin domain containing 2 2641 (NLRP2), transcript variant 1,mRNA. NLRX1 NM 024618 Homo sapiens NLR family member X1 (NLRX1),transcript 2642 variant 1, mRNA. NLRX1 NM 170722 Homo sapiens NLR familymember X1 (NLRX1), transcript 2643 variant 2, mRNA. NOD1 NM 006092 Homosapiens nucleotide-binding oligomerization domain 2644 containing 1(NOD1), mRNA. NOP10 NM 018648 Homo sapiens NOP10 ribonucleoprotein(NOP10), mRNA. 2645 NSMCE3 NM 138704.3 Homo sapiens NSE3 homolog,SMC5-SMC6 complex 2646 component OAS1 NM 001032409 Homo sapiens2′-5′-oligoadenylate synthetase 1, 40/46 kDa 2647 (OAS1), transcriptvariant 3, mRNA. OAS1 NM 002534 Homo sapiens 2′-5′-oligoadenylatesynthetase 1, 40/46 kDa 2648 (OAS1), transcript variant 2, mRNA. OAS1 NM016816 Homo sapiens 2′-5′-oligoadenylate synthetase 1, 40/46 kDa 2649(OAS1), transcript variant 1, mRNA. OAS2 NM 001032731 Homo sapiens2′-5′-oligoadenylate synthetase 2, 69/71 kDa 2650 (OAS2), transcriptvariant 3, mRNA. OAS2 NM 002535 Homo sapiens 2′-5′-oligoadenylatesynthetase 2, 69/71 kDa 2651 (OAS2), transcript variant 2, mRNA. OAS2 NM016817 Homo sapiens 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 2652(OAS2), transcript variant 1, mRNA. OAS3 NM 006187 Homo sapiens2′-5′-oligoadenylate synthetase 3, 100 kDa 2653 (OAS3), mRNA. OASL NM001261825 Homo sapiens 2′-5′-oligoadenylate synthetase-like (OASL), 2654transcript variant 3, mRNA. OASL NM 003733 Homo sapiens2′-5′-oligoadenylate synthetase-like (OASL), 2655 transcript variant 1,mRNA. OASL NM 198213 Homo sapiens 2′-5′-oligoadenylate synthetase-like(OASL), 2656 transcript variant 2, mRNA. ORC4 NM 001190879 Homo sapiensorigin recognition complex, subunit 4 2657 (ORC4), transcript variant 4,mRNA. ORC4 NM 001190881 Homo sapiens origin recognition complex, subunit4 2658 (ORC4), transcript variant 5, mRNA. ORC4 NM 001190882 Homosapiens origin recognition complex, subunit 4 2659 (ORC4), transcriptvariant 6, mRNA. ORC4 NM 002552 Homo sapiens origin recognition complex,subunit 4 2660 (ORC4), transcript variant 2, mRNA. ORC4 NM 181741 Homosapiens origin recognition complex, subunit 4 2661 (ORC4), transcriptvariant 1, mRNA. ORC4 NM 181742 Homo sapiens origin recognition complex,subunit 4 2662 (ORC4), transcript variant 3, mRNA. OTULIN NM 138348.5Homo sapiens OTU deubiquitinase with linear linkage 2663 specificityPARN NM 001134477 Homo sapiens poly(A)-specific ribonuclease (PARN),2664 transcript variant 2, mRNA. PARN NM 001242992 Homo sapienspoly(A)-specific ribonuclease (PARN), 2665 transcript variant 3, mRNA.PARN NM 002582 Homo sapiens poly(A)-specific ribonuclease (PARN), 2666transcript variant 1, mRNA. PCCA NM 000282 Homo sapiens propionyl CoAcarboxylase, alpha 2667 polypeptide (PCCA), transcript variant 1, mRNA.PCCA NM 001127692 Homo sapiens propionyl CoA carboxylase, alpha 2668polypeptide (PCCA), transcript variant 2, mRNA. PCCA NM 001178004 Homosapiens propionyl CoA carboxylase, alpha 2669 polypeptide (PCCA),transcript variant 3, mRNA. PCCB NM 000532 Homo sapiens propionyl CoAcarboxylase, beta polypeptide 2670 (PCCB), transcript variant 1, mRNA.PCCB NM 001178014 Homo sapiens propionyl CoA carboxylase, betapolypeptide 2671 (PCCB), transcript variant 2, mRNA. PDCD1 NM 005018Homo sapiens programmed cell death 1 (PDCD1), mRNA. 2672 PDCD1LG2 NM025239 Homo sapiens programmed cell death 1 ligand 2 2673 (PDCD1LG2),mRNA. PEPD NM 000285 Homo sapiens peptidase D (PEPD), transcript variant1, 2674 mRNA. PEPD NM 001166056 Homo sapiens peptidase D (PEPD),transcript variant 2, 2675 mRNA. PEPD NM 001166057 Homo sapienspeptidase D (PEPD), transcript variant 3, 2676 mRNA. PINK1 NM 032409Homo sapiens PTEN induced putative kinase 1 (PINK1), 2677 mRNA. PLAU NM001145031 Homo sapiens plasminogen activator, urokinase (PLAU), 2678transcript variant 2, mRNA. PLAU NM 002658 Homo sapiens plasminogenactivator, urokinase (PLAU), 2679 transcript variant 1, mRNA. PLAUR NM001005376 Homo sapiens plasminogen activator, urokinase receptor 2680(PLAUR), transcript variant 2, mRNA. PLAUR NM 001005377 Homo sapiensplasminogen activator, urokinase receptor 2681 (PLAUR), transcriptvariant 3, mRNA. PLAUR NM 002659 Homo sapiens plasminogen activator,urokinase receptor 2682 (PLAUR), transcript variant 1, mRNA. PLCG1 NM002660 Homo sapiens phospholipase C, gamma 1 (PLCG1), 2683 transcriptvariant 1, mRNA. PLCG1 NM 182811 Homo sapiens phospholipase C, gamma 1(PLCG1), 2684 transcript variant 2, mRNA. PLD1 NM 001130081 Homo sapiensphospholipase D1, phosphatidylcholine- 2685 specific (PLD1), transcriptvariant 2, mRNA. PLD1 NM 002662 Homo sapiens phospholipase D1,phosphatidylcholine- 2686 specific (PLD1), transcript variant 1, mRNA.PLEKHM1 NM 014798 Homo sapiens pleckstrin homology domain containing,2687 family M (with RUN domain) member 1 (PLEKHM1), transcript variant1, mRNA. PLEKHM1 NR 027774 Homo sapiens pleckstrin homology domaincontaining, 2688 family M (with RUN domain) member 1 (PLEKHM1),transcript variant 2, non-coding RNA. PLEKHM1 NR 027782 Homo sapienspleckstrin homology domain containing, 2689 family M (with RUN domain)member 1 (PLEKHM1), transcript variant 3, non-coding RNA. PLK1 NM 005030Homo sapiens polo-like kinase 1 (PLK1), mRNA. 2690 PLXNB1 NM 001130082Homo sapiens plexin B1 (PLXNB1), transcript variant 2, 2691 mRNA. PLXNB1NM 002673 Homo sapiens plexin B1 (PLXNB1), transcript variant 1, 2692mRNA. PMM2 NM 000303 Homo sapiens phosphomannomutase 2 (PMM2), mRNA.2693 POLE2 NM 001197330 Homo sapiens polymerase (DNA directed), epsilon2, 2694 accessory subunit (POLE2), transcript variant 2, mRNA. POLE2 NM001197331 Homo sapiens polymerase (DNA directed), epsilon 2, 2695accessory subunit (POLE2), transcript variant 3, mRNA. POLE2 NM 002692Homo sapiens polymerase (DNA directed), epsilon 2, 2696 accessorysubunit (POLE2), transcript variant 1, mRNA. PPM1A NM 021003 Homosapiens protein phosphatase, Mg2+/Mn2+ dependent, 2697 1A (PPM1A),transcript variant 1, mRNA. PPM1A NM 177951 Homo sapiens proteinphosphatase, Mg2+/Mn2+ dependent, 2698 1A (PPM1A), transcript variant 2,mRNA. PPM1A NM 177952 Homo sapiens protein phosphatase, Mg2+/Mn2+dependent, 2699 1A (PPM1A), transcript variant 3, mRNA. PRKN NM 004562.2Homo sapiens parkin RBR E3 ubiquitin protein ligase, 2700 transcriptvariant 1 PRKN NM 013987.2 Homo sapiens parkin RBR E3 ubiquitin proteinligase, 2701 transcript variant 2 PRKN NM 013988.2 Homo sapiens parkinRBR E3 ubiquitin protein ligase, 2702 transcript variant 3 PRRC2A NM004638 Homo sapiens proline-rich coiled-coil 2A (PRRC2A), 2703transcript variant 2, mRNA. PRRC2A NM 080686 Homo sapiens proline-richcoiled-coil 2A (PRRC2A), 2704 transcript variant 1, mRNA. PSEN1 NM000021 Homo sapiens presenilin 1 (PSEN1), transcript variant 1, 2705mRNA. PSEN1 NM 007318 Homo sapiens presenilin 1 (PSEN1), transcriptvariant 2, 2706 mRNA. PSENEN NM 172341 Homo sapiens presenilin enhancer2 homolog (C. elegans) 2707 (PSENEN), transcript variant 1, mRNA. PSMA7NM 002792 Homo sapiens proteasome (prosome, macropain) subunit, 2708alpha type, 7 (PSMA7), mRNA. RAB5A NM 004162 Homo sapiens RAB5A, memberRAS oncogene family 2709 (RAB5A), mRNA. RAB5B NM 001252036 Homo sapiensRAB5B, member RAS oncogene family 2710 (RAB5B), transcript variant 2,mRNA. RAB5B NM 001252037 Homo sapiens RAB5B, member RAS oncogene family2711 (RABSB), transcript variant 3, mRNA. RAB5B NM 002868 Homo sapiensRAB5B, member RAS oncogene family 2712 (RAB5B), transcript variant 1,mRNA. RAB5C NM 001252039 Homo sapiens RAB5C, member RAS oncogene family2713 (RAB5C), transcript variant 3, mRNA. RAB5C NM 004583 Homo sapiensRAB5C, member RAS oncogene family 2714 (RAB5C), transcript variant 2,mRNA. RAB5C NM 201434 Homo sapiens RAB5C, member RAS oncogene family2715 (RAB5C), transcript variant 1, mRNA. RAD50 NM 005732 Homo sapiensRAD50 homolog (S. cerevisiae) (RAD50), 2716 mRNA. RANBP2 NM 006267 Homosapiens RAN binding protein 2 (RANBP2), mRNA. 2717 RASGRP1 NM 001128602Homo sapiens RAS guanyl releasing protein 1 (calcium and 2718DAG-regulated) (RASGRP1), transcript variant 2, mRNA. RASGRP1 NM 005739Homo sapiens RAS guanyl releasing protein 1 (calcium and 2719DAG-regulated) (RASGRP1), transcript variant 1, mRNA. RELA NM 001145138Homo sapiens v-rel avian reticuloendotheliosis viral 2720 oncogenehomolog A (RELA), transcript variant 2, mRNA. RELA NM 001243984 Homosapiens v-rel avian reticuloendotheliosis viral 2721 oncogene homolog A(RELA), transcript variant 3, mRNA. RELA NM 001243985 Homo sapiens v-relavian reticuloendotheliosis viral 2722 oncogene homolog A (RELA),transcript variant 4, mRNA. RELA NM 021975 Homo sapiens v-rel avianreticuloendotheliosis viral 2723 oncogene homolog A (RELA), transcriptvariant 1, mRNA. RELB NM 006509 Homo sapiens v-rel avianreticuloendotheliosis viral 2724 oncogene homolog B (RELB), mRNA. RHOHNM 004310 Homo sapiens ras homolog family member H (RHOH), 2725transcript variant 6, mRNA. RLTPR NM 001013838 Homo sapiens RGD motif,leucine rich repeats, 2726 tropomodulin domain and proline-richcontaining (RLTPR), mRNA. RNF125 NM 017831 Homo sapiens ring fingerprotein 125, E3 ubiquitin protein 2727 ligase (RNF125), mRNA. RORC NM001001523 Homo sapiens RAR-related orphan receptor C (RORC), 2728transcript variant 2, mRNA. RORC NM 005060 Homo sapiens RAR-relatedorphan receptor C (RORC), 2729 transcript variant 1, mRNA. RPSA NM001012321 Homo sapiens ribosomal protein SA (RPSA), transcript 2730variant 2, mRNA. RPSA NM 002295 Homo sapiens ribosomal protein SA(RPSA), transcript 2731 variant 1, mRNA. RSAD2 NM 080657 Homo sapiensradical S-adenosyl methionine domain 2732 containing 2 (RSAD2), mRNA.SAMD9 NM 001193307 Homo sapiens sterile alpha motif domain containing 92733 (SAMD9), transcript variant 2, mRNA. SAMD9 NM 017654 Homo sapienssterile alpha motif domain containing 9 2734 (SAMD9), transcript variant1, mRNA. SAMD9L NM 152703 Homo sapiens sterile alpha motif domaincontaining 9-like 2735 (SAMD9L), mRNA. SEMA3E NM 001178129 Homo sapienssema domain, immunoglobulin domain (Ig), 2736 short basic domain,secreted, (semaphorin) 3E (SEMA3E), transcript variant 2, mRNA. SEMA3ENM 012431 Homo sapiens sema domain, immunoglobulin domain (Ig), 2737short basic domain, secreted, (semaphorin) 3E (SEMA3E), transcriptvariant 1, mRNA. SERPINA1 NM 000295 Homo sapiens serpin peptidaseinhibitor, clade A (alpha-1 2738 antiproteinase, antitrypsin), member 1(SERPINA1), transcript variant 1, mRNA. SERPINA1 NM 001002235 Homosapiens serpin peptidase inhibitor, clade A (alpha-1 2739antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 3,mRNA. SERPINA1 NM 001002236 Homo sapiens serpin peptidase inhibitor,clade A (alpha-1 2740 antiproteinase, antitrypsin), member 1 (SERPINA1),transcript variant 2, mRNA. SERPINA1 NM 001127700 Homo sapiens serpinpeptidase inhibitor, clade A (alpha-1 2741 antiproteinase, antitrypsin),member 1 (SERPINA1), transcript variant 4, mRNA. SERPINA1 NM 001127701Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2742antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 5,mRNA. SERPINA1 NM 001127702 Homo sapiens serpin peptidase inhibitor,clade A (alpha-1 2743 antiproteinase, antitrypsin), member 1 (SERPINA1),transcript variant 6, mRNA. SERPINA1 NM 001127703 Homo sapiens serpinpeptidase inhibitor, clade A (alpha-1 2744 antiproteinase, antitrypsin),member 1 (SERPINA1), transcript variant 7, mRNA. SERPINA1 NM 001127704Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2745antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 8,mRNA. SERPINA1 NM 001127705 Homo sapiens serpin peptidase inhibitor,clade A (alpha-1 2746 antiproteinase, antitrypsin), member 1 (SERPINA1),transcript variant 9, mRNA. SERPINA1 NM 001127706 Homo sapiens serpinpeptidase inhibitor, clade A (alpha-1 2747 antiproteinase, antitrypsin),member 1 (SERPINA1), transcript variant 10, mRNA. SERPINA1 NM 001127707Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2748antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant11, mRNA. SERPINB2 NM 001143818 Homo sapiens serpin peptidase inhibitor,clade B 2749 (ovalbumin), member 2 (SERPINB2), transcript variant 1,mRNA. SERPINB2 NM 002575 Homo sapiens serpin peptidase inhibitor, cladeB 2750 (ovalbumin), member 2 (SERPINB2), transcript variant 2, mRNA.SERPING1 NM 000062 Homo sapiens serpin peptidase inhibitor, clade G (C12751 inhibitor), member 1 (SERPING1), transcript variant 1, mRNA.SERPING1 NM 001032295 Homo sapiens serpin peptidase inhibitor, clade G(C1 2752 inhibitor), member 1 (SERPING1), transcript variant 2, mRNA.SH3BP2 NM 001122681 Homo sapiens SH3-domain binding protein 2 (SH3BP2),2753 transcript variant 2, mRNA. SH3BP2 NM 001145855 Homo sapiensSH3-domain binding protein 2 (SH3BP2), 2754 transcript variant 4, mRNA.SH3BP2 NM 001145856 Homo sapiens SH3-domain binding protein 2 (SH3BP2),2755 transcript variant 3, mRNA. SH3BP2 NM 003023 Homo sapiensSH3-domain binding protein 2 (SH3BP2), 2756 transcript variant 1, mRNA.SLC29A3 NM 001174098 Homo sapiens solute carrier family 29(equilibrative 2757 nucleoside transporter), member 3 (SLC29A3),transcript variant 2, mRNA. SLC29A3 NM 018344 Homo sapiens solutecarrier family 29 (equilibrative 2758 nucleoside transporter), member 3(SLC29A3), transcript variant 1, mRNA. SLC29A3 NR 033413 Homo sapienssolute carrier family 29 (equilibrative 2759 nucleoside transporter),member 3 (SLC29A3), transcript variant 3, non-coding RNA. SLC29A3 NR033414 Homo sapiens solute carrier family 29 (equilibrative 2760nucleoside transporter), member 3 (SLC29A3), transcript variant 4,non-coding RNA. SLC35C1 NM 001145265 Homo sapiens solute carrier family35 (GDP-fucose 2761 transporter), member C1 (SLC35C1), transcriptvariant 2, mRNA. SLC35C1 NM 001145266 Homo sapiens solute carrier family35 (GDP-fucose 2762 transporter), member C1 (SLC35C1), transcriptvariant 3, mRNA. SLC35C1 NM 018389 Homo sapiens solute carrier family 35(GDP-fucose 2763 transporter), member C1 (SLC35C1), transcript variant1, mRNA. SLC7A7 NM 001126105 Homo sapiens solute carrier family 7 (aminoacid transporter 2764 light chain, y + L system), member 7 (SLC7A7),transcript variant 2, mRNA. SLC7A7 NM 001126106 Homo sapiens solutecarrier family 7 (amino acid transporter 2765 light chain, y + Lsystem), member 7 (SLC7A7), transcript variant 3, mRNA. SLC7A7 NR 040448Homo sapiens solute carrier family 7 (amino acid transporter 2766 lightchain, y + L system), member 7 (SLC7A7), transcript variant 1,non-coding RNA. SLC9A1 NM 003047 Homo sapiens solute carrier family 9,subfamily A (NHE1, 2767 cation proton antiporter 1), member 1 (SLC9A1),transcript variant 1, mRNA. SLC9A1 NR 046474 Homo sapiens solute carrierfamily 9, subfamily A (NHE1, 2768 cation proton antiporter 1), member 1(SLC9A1), transcript variant 2, non-coding RNA. SMARCAL1 NM 001127207Homo sapiens SWI/SNF related, matrix associated, actin 2769 dependentregulator of chromatin, subfamily a-like 1 (SMARCAL1), transcriptvariant 2, mRNA. SMARCAL1 NM 014140 Homo sapiens SWI/SNF related, matrixassociated, actin 2770 dependent regulator of chromatin, subfamilya-like 1 (SMARCAL1), transcript variant 1, mRNA. SMARCD2 NM 001098426Homo sapiens SWI/SNF related, matrix associated, actin 2771 dependentregulator of chromatin, subfamily d, member 2 (SMARCD2), mRNA. SMC3 NM005445 Homo sapiens structural maintenance of chromosomes 3 2772 (SMC3),mRNA. SMURF2 NM 022739 Homo sapiens SMAD specific E3 ubiquitin proteinligase 2 2773 (SMURF2), mRNA. SRP54 NM 001146282 Homo sapiens signalrecognition particle 54 kDa (SRP54), 2774 transcript variant 2, mRNA.SRP54 NM 003136 Homo sapiens signal recognition particle 54 kDa (SRP54),2775 transcript variant 1, mRNA. STN1 NM 024928.4 Homo sapiens STN1, CSTcomplex subunit 2776 TBC1D15 NM 001146213 Homo sapiens TBC1 domainfamily, member 15 2777 (TBC1D15), transcript variant 3, mRNA. TBC1D15 NM001146214 Homo sapiens TBC1 domain family, member 15 2778 (TBC1D15),transcript variant 2, mRNA. TBC1D15 NM 022771 Homo sapiens TBC1 domainfamily, member 15 2779 (TBC1D15), transcript variant 1, mRNA. TBC1D15 NR027449 Homo sapiens TBC1 domain family, member 15 2780 (TBC1D15),transcript variant 4, non-coding RNA. TBC1D17 NM 001168222 Homo sapiensTBC1 domain family, member 17 2781 (TBC1D17), transcript variant 2,mRNA. TBC1D17 NM 024682 Homo sapiens TBC1 domain family, member 17 2782(TBC1D17), transcript variant 1, mRNA. TCF3 NM 001136139 Homo sapienstranscription factor 3 (TCF3), transcript 2783 variant 2, mRNA. TCF3 NM003200 Homo sapiens transcription factor 3 (TCF3), transcript 2784variant 1, mRNA. TCN2 NM 000355 Homo sapiens transcobalamin II (TCN2),transcript variant 2785 1, mRNA. TCN2 NM 001184726 Homo sapienstranscobalamin II (TCN2), transcript variant 2786 2, mRNA. TEK NM 000459Homo sapiens TEK tyrosine kinase, endothelial (TEK), 2787 mRNA. TERC NR001566 Homo sapiens telomerase RNA component (TERC), 2788 telomeraseRNA. TERT NM 001193376 Homo sapiens telomerase reverse transcriptase(TERT), 2789 transcript variant 2, mRNA. TERT NM 198253 Homo sapienstelomerase reverse transcriptase (TERT), 2790 transcript variant 1,mRNA. TFPI NM 001032281 Homo sapiens tissue factor pathway inhibitor(lipoprotein- 2791 associated coagulation inhibitor) (TFPI), transcriptvariant 2, mRNA. TFPI NM 006287 Homo sapiens tissue factor pathwayinhibitor (lipoprotein- 2792 associated coagulation inhibitor) (TFPI),transcript variant 1, mRNA. TFRC NM 001128148 Homo sapiens transferrinreceptor (p90, CD71) (TFRC), 2793 transcript variant 2, mRNA. TFRC NM003234 Homo sapiens transferrin receptor (p90, CD71) (TFRC), 2794transcript variant 1, mRNA. THBD NM 000361 Homo sapiens thrombomodulin(THBD), mRNA. 2795 THBS1 NM 003246 Homo sapiens thrombospondin 1(THBS1), mRNA. 2796 TINF2 NM 001099274 Homo sapiens TERF1(TRF1)-interacting nuclear factor 2 2797 (TINF2). transcript variant 1,mRNA. TINF2 NM 012461 Homo sapiens TERF1 (TRF1)-interacting nuclearfactor 2 2798 (TINF2), transcript variant 2, mRNA. TIRAP NM 001039661Homo sapiens toll-interleukin 1 receptor (TIR) domain 2799 containingadaptor protein (TIRAP), transcript variant 3, mRNA. TIRAP NM 148910Homo sapiens toll-interleukin 1 receptor (TIR) domain 2800 containingadaptor protein (TIRAP), transcript variant 2, mRNA. TMC6 NM 001127198Homo sapiens transmembrane channel-like 6 (TMC6), 2801 transcriptvariant 1, mRNA. TMC6 NM 007267 Homo sapiens transmembrane channel-like6 (TMC6), 2802 transcript variant 2, mRNA. TMC8 NM 152468 Homo sapienstransmembrane channel-like 8 (TMC8), 2803 mRNA. TNFRSF17 NM 001192 Homosapiens tumor necrosis factor receptor superfamily, 2804 member 17(TNFRSF17), mRNA. TNFRSF1A NM 001065 Homo sapiens tumor necrosis factorreceptor superfamily, 2805 member 1A (TNFRSF1A), mRNA. TNFSF10 NM001190942 Homo sapiens tumor necrosis factor (ligand) superfamily, 2806member 10 (TNFSF10), transcript variant 2, mRNA. TNFSF10 NM 001190943Homo sapiens tumor necrosis factor (ligand) superfamily, 2807 member 10(TNFSF10), transcript variant 3, mRNA. TNFSF10 NM 003810 Homo sapienstumor necrosis factor (ligand) superfamily, 2808 member 10 (TNFSF10),transcript variant 1, mRNA. TNFSF10 NR 033994 Homo sapiens tumornecrosis factor (ligand) superfamily, 2809 member 10 (TNFSF10),transcript variant 4, non-coding RNA. TNFSF13 NM 001198622 Homo sapienstumor necrosis factor (ligand) superfamily, 2810 member 13 (TNFSF13),transcript variant delta, mRNA. TNFSF13 NM 001198623 Homo sapiens tumornecrosis factor (ligand) superfamily, 2811 member 13 (TNFSF13),transcript variant zeta, mRNA. TNFSF13 NM 001198624 Homo sapiens tumornecrosis factor (ligand) superfamily, 2812 member 13 (TNFSF13),transcript variant eta, mRNA. TNFSF13 NM 003808 Homo sapiens tumornecrosis factor (ligand) superfamily, 2813 member 13 (TNFSF13),transcript variant alpha, mRNA. TNFSF13 NM 172087 Homo sapiens tumornecrosis factor (ligand) superfamily, 2814 member 13 (TNFSF13),transcript variant beta, mRNA. TNFSF13 NM 172088 Homo sapiens tumornecrosis factor (ligand) superfamily, 2815 member 13 (TNFSF13),transcript variant gamma, mRNA. TNFSF13 NR 073490 Homo sapiens tumornecrosis factor (ligand) superfamily, 2816 member 13 (TNFSF13),transcript variant episilon, non- coding RNA. TNFSF13B NM 001145645 Homosapiens tumor necrosis factor (ligand) superfamily, 2817 member 13b(TNFSF13B), transcript variant 2, mRNA. TNFSF13B NM 006573 Homo sapienstumor necrosis factor (ligand) superfamily, 2818 member 13b (TNFSF13B),transcript variant 1, mRNA. TNIP1 NM 001252385 Homo sapiens TNFAIP3interacting protein 1 (TNIP1), 2819 transcript variant 1, mRNA. TNIP1 NM001252386 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2820transcript variant 2, mRNA. TNIP1 NM 001252390 Homo sapiens TNFAIP3interacting protein 1 (TNIP1), 2821 transcript variant 3, mRNA. TNIP1 NM001252391 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2822transcript variant 4, mRNA. TNIP1 NM 001252392 Homo sapiens TNFAIP3interacting protein 1 (TNIP1), 2823 transcript variant 6, mRNA. TNIP1 NM001252393 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2824transcript variant 7, mRNA. TNIP1 NM 001258454 Homo sapiens TNFAIP3interacting protein 1 (TNIP1), 2825 transcript variant 8, mRNA. TNIP1 NM001258455 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2826transcript variant 9, mRNA. TNIP1 NM 001258456 Homo sapiens TNFAIP3interacting protein 1 (TNIP1), 2827 transcript variant 10, mRNA. TNIP1NM 006058 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2828transcript variant 5, mRNA. TP53AIP1 NM 001195194 Homo sapiens tumorprotein p53 regulated apoptosis 2829 inducing protein 1 (TP53AIP1),transcript variant 3, mRNA. TP53AIP1 NM 001195195 Homo sapiens tumorprotein p53 regulated apoptosis 2830 inducing protein 1 (TP53AIP1),transcript variant 2, mRNA. TP53AIP1 NM 001251964 Homo sapiens tumorprotein p53 regulated apoptosis 2831 inducing protein 1 (TP53AIP1),transcript variant 4, mRNA. TP53AIP1 NM 022112 Homo sapiens tumorprotein p53 regulated apoptosis 2832 inducing protein 1 (TP53AIP1),transcript variant 1, mRNA. TPP1 NM 000391 Homo sapiens tripeptidylpeptidase I (TPP1), mRNA. 2833 TPP2 NM 003291 Homo sapiens tripeptidylpeptidase II (TPP2), mRNA. 2834 TRAF3IP2 NM 001164281 Homo sapiens TRAF3interacting protein 2 (TRAF3IP2), 2835 transcript variant 3, mRNA.TRAF3IP2 NM 001164283 Homo sapiens TRAF3 interacting protein 2(TRAF3IP2), 2836 transcript variant 5, mRNA. TRAF3IP2 NM 147686 Homosapiens TRAF3 interacting protein 2 (TRAF3IP2), 2837 transcript variant2, mRNA. TRAF3IP2 NR 028338 Homo sapiens TRAF3 interacting protein 2(TRAF3IP2), 2838 transcript variant 1, non-coding RNA. TRIM25 NM 005082Homo sapiens tripartite motif containing 25 (TRIM25), 2839 mRNA. TRIM37NM 001005207 Homo sapiens tripartite motif containing 37 (TRIM37), 2840transcript variant 2, mRNA. TRIM37 NM 015294 Homo sapiens tripartitemotif containing 37 (TRIM37), 2841 transcript variant 1, mRNA. TTC37 NM014639 Homo sapiens tetratricopeptide repeat domain 37 (TTC37), 2842mRNA. UBD NM 006398 Homo sapiens ubiquitin D (UBD), mRNA. 2843 USB1 NM001195302 Homo sapiens U6 snRNA biogenesis 1 (USB1), transcript 2844variant 2, mRNA. USB1 NM 001204911 Homo sapiens U6 snRNA biogenesis 1(USB1), transcript 2845 variant 3, mRNA. USB1 NM 024598 Homo sapiens U6snRNA biogenesis 1 (USB1), transcript 2846 variant 1, mRNA. USP15 NM001252078 Homo sapiens ubiquitin specific peptidase 15 (USP15), 2847transcript variant 1, mRNA. USP15 NM 001252079 Homo sapiens ubiquitinspecific peptidase 15 (USP15), 2848 transcript variant 3, mRNA. USP15 NM006313 Homo sapiens ubiquitin specific peptidase 15 (USP15), 2849transcript variant 2, mRNA. USP21 NM 001014443 Homo sapiens ubiquitinspecific peptidase 21 (USP21), 2850 transcript variant 3, mRNA. USP21 NM012475 Homo sapiens ubiquitin specific peptidase 21 (USP21), 2851transcript variant 1, mRNA. USP25 NM 013396 Homo sapiens ubiquitinspecific peptidase 25 (USP25), 2852 mRNA. USP3 NM 001256702 Homo sapiensubiquitin specific peptidase 3 (USP3), 2853 transcript variant 2, mRNA.USP3 NM 006537 Homo sapiens ubiquitin specific peptidase 3 (USP3), 2854transcript variant 1, mRNA. USP3 NR 046341 Homo sapiens ubiquitinspecific peptidase 3 (USP3), 2855 transcript variant 3, non-coding RNA.USP3 NR 046342 Homo sapiens ubiquitin specific peptidase 3 (USP3), 2856transcript variant 4, non-coding RNA. VAV1 NM 001258206 Homo sapiens vav1 guanine nucleotide exchange factor 2857 (VAV1), transcript variant 2,mRNA. VAV1 NM 001258207 Homo sapiens vav 1 guanine nucleotide exchangefactor 2858 (VAV1), transcript variant 3, mRNA. VAV1 NM 005428 Homosapiens vav 1 guanine nucleotide exchange factor 2859 (VAV1), transcriptvariant 1, mRNA. VDR NM 000376 Homo sapiens vitamin D(1,25-dihydroxyvitamin D3) 2860 receptor (VDR), transcript variant 1,mRNA. VDR NM 001017535 Homo sapiens vitamin D (1,25-dihydroxyvitamin D3)2861 receptor (VDR), transcript variant 2, mRNA. VDR NM 001017536 Homosapiens vitamin D (1,25-dihydroxyvitamin D3) 2862 receptor (VDR),transcript variant 3, mRNA. VEGFA NM 001025366 Homo sapiens vascularendothelial growth factor A 2863 (VEGFA), transcript variant 1, mRNA.VEGFA NM 001025367 Homo sapiens vascular endothelial growth factor A2864 (VEGFA), transcript variant 3, mRNA. VEGFA NM 001025368 Homosapiens vascular endothelial growth factor A 2865 (VEGFA), transcriptvariant 4, mRNA. VEGFA NM 001025369 Homo sapiens vascular endothelialgrowth factor A 2866 (VEGFA), transcript variant 5, mRNA. VEGFA NM001025370 Homo sapiens vascular endothelial growth factor A 2867(VEGFA), transcript variant 6, mRNA. VEGFA NM 001033756 Homo sapiensvascular endothelial growth factor A 2868 (VEGFA), transcript variant 7,mRNA. VEGFA NM 001171622 Homo sapiens vascular endothelial growth factorA 2869 (VEGFA), transcript variant 8, mRNA. VEGFA NM 001171623 Homosapiens vascular endothelial growth factor A 2870 (VEGFA), transcriptvariant 1, mRNA. VEGFA NM 001171624 Homo sapiens vascular endothelialgrowth factor A 2871 (VEGFA), transcript variant 2, mRNA. VEGFA NM001171625 Homo sapiens vascular endothelial growth factor A 2872(VEGFA), transcript variant 3, mRNA. VEGFA NM 001171626 Homo sapiensvascular endothelial growth factor A 2873 (VEGFA), transcript variant 4,mRNA. VEGFA NM 001171627 Homo sapiens vascular endothelial growth factorA 2874 (VEGFA), transcript variant 5, mRNA. VEGFA NM 001171628 Homosapiens vascular endothelial growth factor A 2875 (VEGFA), transcriptvariant 6, mRNA. VEGFA NM 001171629 Homo sapiens vascular endothelialgrowth factor A 2876 (VEGFA), transcript variant 7, mRNA. VEGFA NM001171630 Homo sapiens vascular endothelial growth factor A 2877(VEGFA), transcript variant 8, mRNA. VEGFA NM 001204384 Homo sapiensvascular endothelial growth factor A 2878 (VEGFA), transcript variant 9,mRNA. VEGFA NM 001204385 Homo sapiens vascular endothelial growth factorA 2879 (VEGFA), transcript variant 9, mRNA. VEGFA NM 003376 Homo sapiensvascular endothelial growth factor A 2880 (VEGFA), transcript variant 2,mRNA. WASHC5 NM 001330609.1 Homo sapiens WASH complex subunit 5,transcript variant 2881 2 WASHC5 NM 014846.3 Homo sapiens WASH complexsubunit 5, transcript variant 2882 1 WDR1 NM 005112 Homo sapiens WDrepeat domain 1 (WDR1), transcript 2883 variant 2, mRNA. WDR1 NM 017491Homo sapiens WD repeat domain 1 (WDR1), transcript 2884 variant 1, mRNA.WRAP53 NM 001143990 Homo sapiens WD repeat containing, antisense to TP532885 (WRAP53), transcript variant 2, mRNA. WRAP53 NM 001143991 Homosapiens WD repeat containing, antisense to TP53 2886 (WRAP53),transcript variant 3, mRNA. WRAP53 NM 001143992 Homo sapiens WD repeatcontaining, antisense to TP53 2887 (WRAP53), transcript variant 4, mRNA.WRAP53 NM 018081 Homo sapiens WD repeat containing, antisense to TP532888 (WRAP53), transcript variant 1, mRNA. XAF1 NM 017523 Homo sapiensXIAP associated factor 1 (XAF1), transcript 2889 variant 1, mRNA. XAF1NM 199139 Homo sapiens XIAP associated factor 1 (XAF1), transcript 2890variant 2, mRNA. XAF1 NR 046396 Homo sapiens XIAP associated factor 1(XAF1), transcript 2891 variant 3, non-coding RNA. XAF1 NR 046397 Homosapiens XIAP associated factor 1 (XAF1), transcript 2892 variant 4,non-coding RNA. XAF1 NR 046398 Homo sapiens XIAP associated factor 1(XAF1), transcript 2893 variant 5, non-coding RNA.Table 32 represents a non-redundant list of transcript variants thatcorrespond to the Table 31 genes.

TABLE 33 SEQ ID 3000-3274, SNV list (Tables 34-36, 38, 39) with SEQ IDnumbers (similar to Table 5) Chromosome Position (hg19) Ref Allele AltAllele SEQ ID 1 11087369 T C 3000 1 11090287 C T 3001 1 11090916 C A3002 1 11094908 T A 3003 1 11106648 G A 3004 1 11106666 T C 3005 111106673 G A 3006 1 12049283 C T 3007 1 12064892 G A 3008 1 12064931 G A3009 1 57333311 C A 3010 1 57372463 C T 3011 1 57373778 G A 3012 157378149 G T 3013 1 57383295 G A 3014 1 57409459 C A 3015 1 57422511 C T3016 1 59131311 G T 3017 1 82409337 A G 3018 1 82416040 C T 3019 182450271 G A 3020 1 82456165 G T 3021 1 160281740 T C 3022 1 183532364 TA 3023 1 196709774 G T 3024 1 196759282 C T 3025 1 196794681 G T 3026 1196799813 G A 3027 1 196871610 A T 3028 1 196918732 G T 3029 1 196920123G A 3030 1 196973890 G A 3031 2 7027110 G T 3032 2 15432775 C T 3033 215519924 C T 3034 2 15542352 C T 3035 2 15607842 T C 3036 2 15674686 T C3037 2 47637246 A G 3038 2 47702191 A G 3039 2 74688563 C T 3040 274688884 G A 3041 2 74689335 G T 3042 2 74690039 G A 3043 2 74690371 C T3044 2 74690378 C T 3045 2 109381493 G C 3046 2 109382448 C T 3047 2109384800 C T 3048 2 188349523 A G 3049 2 217285060 C G 3050 2 217285104C G 3051 2 217288388 G C 3052 3 11382205 A C 3053 3 11399970 C T 3054 311402163 G A 3055 3 11468330 A G 3056 3 20017123 A C 3057 3 37061893 T C3058 3 37061929 A G 3059 3 37092025 C T 3060 3 39452455 C T 3061 348457498 G C 3062 3 48461135 C T 3063 3 48463544 G A 3064 3 49949430 C T3065 3 171321023 C T 3066 3 171379953 C T 3067 3 171431726 C G 3068 3171455697 G C 3069 3 171455739 A G 3070 4 89352440 A C 3071 4 89414196 GA 3072 4 110864533 C T 3073 4 110865044 G C 3074 4 110866260 G C 3075 4110897252 C G 3076 4 110929301 T C 3077 4 110932508 C A 3078 4 126237697A C 3079 4 126238090 G T 3080 4 126238305 C A 3081 4 126239241 G A 30824 126239253 G C 3083 4 126239421 C T 3084 4 126239623 G A 3085 4126239986 C T 3086 4 126240255 A G 3087 4 126240377 G T 3088 4 126240390A G 3089 4 126240968 A T 3090 4 126241248 C G 3091 4 126241720 T C 30924 126241785 G A 3093 4 126328170 C T 3094 4 126336758 G A 3095 4126336851 G A 3096 4 126372003 A G 3097 4 126372975 A C 3098 4 126373570C T 3099 4 126389832 G A 3100 4 126408663 A G 3101 4 126411179 C T 31024 126411493 C T 3103 4 126412106 C G 3104 4 126412154 G A 3105 4126412226 G A 3106 4 126412634 C G 3107 5 34929974 A T 3108 5 34937524 CT 3109 5 39311336 A T 3110 5 40955561 G C 3111 5 40959622 C T 3112 540964852 A C 3113 5 131925413 A G 3114 5 132015535 C T 3115 5 134076987G C 3116 6 30673403 A G 3117 6 30675830 T A 3118 6 30680721 G A 3119 631593603 A G 3120 6 31595795 C T 3121 6 31595926 C T 3122 6 31597451 G A3123 6 31597469 A C 3124 6 31598524 G A 3125 6 31599370 G C 3126 631600118 G A 3127 6 31600558 C T 3128 6 31600696 G A 3129 6 31600708 G A3130 6 31601735 G A 3131 6 31602967 G A 3132 6 31603045 A G 3133 631604591 C T 3134 6 31604610 T C 3135 6 31604894 C T 3136 6 31605016 T C3137 6 31605278 C T 3138 6 31709045 C T 3139 6 31725978 C G 3140 631729925 C T 3141 6 43748510 G A 3142 6 106740989 T C 3143 6 111913058 GA 3144 6 111913262 C T 3145 7 5959528 T C 3146 7 30491421 G T 3147 730491693 C T 3148 7 74193620 G A 3149 7 80300449 T G 3150 7 92732769 T C3151 7 92733766 C A 3152 7 92761257 A T 3153 7 92763720 G A 3154 7117230454 G C 3155 7 117232086 G A 3156 7 117232223 C T 3157 7 117246776T C 3158 8 11400805 C A 3159 8 11400849 C T 3160 8 11407690 C T 3161 811412934 G A 3162 8 11415492 A C 3163 8 11418856 C T 3164 8 126071726 GA 3165 8 126095371 T C 3166 9 27109600 A C 3167 9 27158131 C T 3168 927183598 C T 3169 9 27197588 C T 3170 9 35612978 G A 3171 9 98678698 G C3172 9 98691137 T C 3173 10 54531226 C T 3174 10 54531235 C T 3175 1054531242 G A 3176 10 75672059 G A 3177 10 75673748 A C 3178 10 75675086T C 3179 10 91098614 G A 3180 10 91162073 T C 3181 11 60891358 C T 318211 60893235 C T 3183 11 65423327 G A 3184 11 72145307 C G 3185 11119045378 C T 3186 11 119045951 C T 3187 11 119052975 G T 3188 11128807550 C G 3189 12 25362788 T A 3190 12 25368449 A T 3191 12 40657700C G 3192 12 40671773 A G 3193 12 40677813 G T 3194 12 40702420 A G 319512 40702910 C T 3196 12 40702911 G A 3197 12 40740686 A G 3198 1249421042 C T 3199 12 49421811 C A 3200 12 49428694 T C 3201 12 49433083G A 3202 12 49433533 G C 3203 12 49440564 C T 3204 12 56383856 A G 320512 56385915 GGGA G 3206 12 113357209 G A 3207 12 113357237 G C 3208 12113357442 G A 3209 12 113403675 C T 3210 12 113405825 G A 3211 12113448288 A G 3212 14 35497285 T C 3213 14 94847262 T A 3214 15 63866584C A 3215 15 93545488 T A 3216 16 11145457 G A 3217 16 11272435 G A 321816 14704607 G A 3219 16 23693443 C T 3220 16 23700676 T A 3221 1658054099 C G 3222 16 67680806 G A 3223 16 67685730 A T 3224 16 67694044C T 3225 16 67694078 G T 3226 16 69725697 T G 3227 16 77225440 G T 322817 6659427 C A 3229 17 7592168 C G 3230 17 8138569 C G 3231 17 41165632G A 3232 17 43555253 A G 3233 17 62582265 T C 3234 17 76129619 C T 323517 76130947 G T 3236 18 29645930 A T 3237 18 57103126 G A 3238 1861570402 G A 3239 19 6707129 G A 3240 19 7754222 G A 3241 19 10394724 CT 3242 19 10395141 G A 3243 19 15383894 C G 3244 19 33892731 A G 3245 1933968991 T A 3246 19 33980963 G A 3247 19 35823528 C T 3248 19 44153248T C 3249 19 49843566 G A 3250 19 50385633 G C 3251 19 55494157 G A 325220 39794388 T C 3253 20 44640275 G A 3254 20 44640959 G A 3255 2135122475 C T 3256 21 35239562 A G 3257 21 42752030 G A 3258 21 42807815A G 3259 21 42807881 G A 3260 21 42812952 G A 3261 21 42813652 C A 326221 42815731 G A 3263 21 42817460 C T 3264 21 42830468 G A 3265 2142830657 G A 3266 21 45708270 T C 3267 21 45708278 G A 3268 21 45713696G A 3269 22 31006882 T G 3270 22 31008867 T C 3271 22 31018975 T C 327222 35806756 G A 3273 22 37271882 T C 3274Table 33 lists a set of SNVs reported in Tables 34-36, 38, or 39 thatwere found in the 70 PML cases for the genes listed in Table 31.

TABLE 34 Case-solving Tier 1 SNVs (het, hom, or phased comp het) withfrequency <=1/1,000 or novel Compound Variant Variant Compound FrequencyFrequency Frequency Frequency RefSeq Amino Details (Reciprocal, Details(Reciprocal, Sample Gene Variant Chromo- Position Ref Alt Acid (EthnicEthnic (Ethnic Ethnic SEQ ID Symbol Type some (hg19) Allele AlleleChange specific) specific) specific) specific) ID MVGS1116- PRRC2A SNV 631601735 G A R1563Q 0.087118 1 in 11 7.40E−04 1 in 1,350 3131 8a hetMVGS1116- PRRC2A SNV 6 31604894 C T R2075W 0.034000 1 in 29 7.40E−04 1in 1,350 3136 8a het MVGS1368 KMT2D SNV 12 49421811 C A K4832N 0.0002401 in n/a n/a 3200 het 4,167 MVGS540- ATG7 SNV 3 11382205 A C K287Q6.14E−25 1 in n/a n/a 3053 374b het 16,292 MVGS540- KMT2D SNV 1249433533 G C Q2674E 0 infinite n/a n/a 3203 374b het MVGS694- AIRE SNV21 45708270 T C M194T 0 infinite n/a n/a 3267 6a het MVGS811- LRRK2 SNV12 40702910 C T R1398C 6.01E−05 1 in 2.09E−06 1 in 3196 13a het 16,646477,620 MVGS811- LRRK2 SNV 12 40702911 G A R1398H 0.139408 1 in 72.09E−06 1 in 3197 13a het 477,620 MVGS811- USP3 SNV 15 63866584 C AP11IT 0.000513 1 in n/a n/a 3215 132 het 1,950 MVGS995- VEGFA SNV 643748510 G A R155H 3.00E−05 1 in n/a n/a 3142 4a het 33,364 PML04 RSAD2SNV 2 7027110 G T E117* 0 infinite n/a n/a 3032 het PML04 IFIT1 SNV 1091162073 T C L14P 0 infinite n/a n/a 3181 he PML04 CLEC16A SNV 1611145457 G A V634M 0.000129 1 in n/a n/a 3217 het 8,339 PML06 LRRK2 SNV12 40657700 C G N299K 0.018554 1 in 54 1.19E−05 1 in 3192 hom 84,337PML06 LRRK2 SNV 12 40671773 A G I423M 0.000194 1 in see het see het 3193het 5,159 SNVs SNVs PML06 LRRK2 SNV 12 40702911 G A R1398H 0.019646 1 in51 1.17E−05 1 in 3197 hom 85,236 PML06 CD37 SNV 19 49843566 G A R208Q0.000194 1 in n/a n/a 3250 het 5,165 PML09 FAT4 SNV 4 126239986 C TA807V 0.196043 1 in 5 0.000273 1 in 3,665 3086 hom PML09 FAT4 SNV 4126241248 C G Q1228E 0.002227 1 in 449 0.000273 1 in 3,665 3091 hetPML09 PRRC2A SNV 6 31600118 G A R1223H 0 infinite n/a n/a 3127 het PML10ATG7 SNV 3 11468330 A G N643S 0 infinite n/a n/a 3056 het PML10 PRRC2ASNV 6 31597469 A C K701Q 0.000186 1 in n/a n/a 3124 het 5,385 PML14 KRASSNV 12 25362788 T A M170L 3.03E−05 1 in n/a n/a 3190 het 33,044 PML15CFHR1 SNV 1 196794681 G T V45F 0.000182 1 in n/a n/a 3026 hom 5,509PML15 CFHR1 SNV 1 196799813 G A n/a 0.000175 1 in n/a n/a 3027 hom 5,711PML15 PRRC2A SNV 6 31598524 G A R804H 0 infinite n/a n/a 3125 het PML15MBL2 SNV 10 54531226 C T G57E 0.000518 1 in n/a n/a 3174 hom 1,929 PML16IFIT3 SNV 10 91098614 G A E68K 0 infinite n/a n/a 3180 het PML17 TEK SNV9 27109600 A C L4F 8.99E−05 1 in n/a n/a 3167 het 11,123 PML17 TEK SNV 927158131 C T RI19C 0 infinite n/a n/a 3168 het PML18 OAS3 SNV 12113403675 C T R844* 0.000277 1 in n/a n/a 3210 hom 3,611 PML19 MASP2 SNV1 11087369 T C N545S 0 infinite 0 infinite 3000 het PML19 MASP2 SNV 111090916 C A D371Y 0.070713 1 in 14 see het see het 3002 hom SNV SNVPML19 ADGRL2 SNV 1 82450271 G A R1017Q 0 infinite n/a n/a 3020 het PML23RANBP2 SNV 2 109382448 C T P1818L 3.00E−05 1 in n/a n/a 3047 het 33,362PML25 ATG7 SNV 3 11399970 C T R416C 6.00E−05 1 in n/a n/a 3054 het16,676 PML25 IL4 SNV 5 132015535 C T R105* 0 infinite n/a n/a 3115 hetPML27 MLH1 SNV 3 37061929 A G N240S 0.000180 1 in n/a n/a 3059 het 5,543PML28 MSH2 SNV 2 47702191 A G N530S 0.00063 1 in n/a n/a 3039 het 1,586PML28 FAT4 SNV 4 126239623 G A S686N 5.99E−05 1 in 7.35E−06 1 in 3085het 16,684 136,129 PML28 FAT4 SNV 4 126239986 C T A807V 0.490241 1 in 27.35E−06 1 in 3086 het 136,129 PML30 MONIA SNV 3 49949430 C T G145S0.000720 1 in n/a n/a 3065 het 1.388 PML31 CFHR5 SNV 1 196973890 G AR477H 0.000577 1 in n/a n/a 3031 het 1,734 PML31 FAT4 SNV 4 126239253 GC V563L 0 infinite 0 infinite 3083 het PML31 FAT4 SNV 4 126239986 C TA807V 0.32551 1 in 3 see het see het 3086 hom 0 SNVs SNVs PML31 FAT4 SNV4 126328170 C T R113C 0 infinite 0 infinite 3094 het PML31 FAT4 SNV 4126372003 A G R1576G 0 infinite 0 infinite 3097 het PML31 PRRC2A SNV 631593603 A G Y265C 0 infinite n/a n/a 3120 het PML31 PRRC2A SNV 631602967 G A R1740H 0.258362 1 in 4 see het see het 3132 hom SNV SNVPML31 RNF125 SNV 18 29645930 A T R190S 0.000190 1 in n/a n/a 3237 hom5,203 PML31 PLCG1 SNV 20 39794388 T C I574T 0 infinite n/a n/a 3253 hetPML32 FAT4 SNV 4 126239986 C T A807V 0.196043 1 in 5 see het see het3086 hom SNV SNV PML32 FAT4 SNV 4 126412226 G A G2991E 0 infinite 0infinite 3106 het PML33 PRRC2A SNV 6 31600558 C T R1370C 3.16E−05 1 inn/a n/a 3128 het 31,613 PML33 KMT2D SNV 12 49440564 C T V1416M 0infinite n/a n/a 3204 het PML35 TP53AIP1 SNV 11 128807550 C G R55P0.000210 1 in n/a n/a 3189 het 4,763 PML35 MX1 SNV 21 42813652 C A T224K0 infinite n/a n/a 3262 het PML37 FAT4 SNV 4 126239986 C T A807V0.325510 1 in 3 2.36E−05 1 in 3086 hom 42,385 PML37 FAT4 SNV 4 126336758G A A2214T 0.000192 1 in 2.36E−05 1 in 3095 het 5,203 42,385 PML38PRRC2A SNV 6 31597451 G A A695T 0 infinite n/a n/a 3123 het PML38 MX1SNV 21 42830657 G A R631Q 3.07E−05 1 in n/a n/a 3266 het 32,566 PML39PRRC2A SNV 6 31600708 G A G1420R 0 infinite n/a n/a 3130 het PML40 COPASNV 1 160281740 T C M332V 0.000692 1 in n/a n/a 3022 het 1,444 PML40MSH2 SNV 2 47637246 A G N127S 0 infinite n/a n/a 3038 hom PML40 TBCID17SNV 19 50385633 G C E225D 0 infinite n/a n/a 3251 het PML41 MLH1 SNV 337061893 T C V228A 0.000577 1 in n/a n/a 3058 het 1,734 PML41 SAMD9L SNV7 92761257 A T L1343H 0 infinite n/a n/a 3153 het PML41 SMURF2 SNV 1762582265 T C I129V 0 infinite n/a n/a 3234 het PML43 KRAS SNV 1225368449 A T Y166N 0.000300 1 in n/a n/a 3191 het 3,335 PML44 RAB5A SNV3 20017123 A C D65A 3.01E−05 1 in n/a n/a 3057 het 33,252 PML44 PLXNB1SNV 3 48461135 C T E854K 0.000705 1 in n/a n/a 3063 het 1,419 PML44 NLRXSNV 11 119045378 C T R356W 0.000992 1 in n/a n/a 3186 het 1,008 PML45 C7SNV 5 40955561 G C S389T 0.472838 1 in 2 3.97E−06 1 in 3111 het 251,629PML45 C7 SNV 5 40959622 C T R521C 3.36E−05 1 in 3.97E−06 1 in 3112 het29,745 251,629 PML45 WASHCS SNV 8 126071726 G A T3791 3.03E−05 1 in n/an/a 3165 het 32,985 PML45 BRD4 SNV 19 15383894 C G G6A 9.24E−05 1 in n/an/a 3244 het 10,823 PML48 NCF1 SNV 7 74193620 G A G83R 6.32E−05 1 in n/an/a 3149 hom 15,829 PML48 MX1 SNV 21 42807815 A G I53V 0.000120 1 in n/an/a 3259 het 8,339 PML49 RPSA SNV 3 39452455 C T R155C 0 infinite n/an/a 3061 het PML49 BLK SNV 8 11400805 C A S24R 3.02E−05 1 in n/a n/a3159 het 33,067 PML51 NBAS SNV 2 15519924 C T R1011H 0.000839 1 in n/an/a 3034 hom 1,191 PML52 KMT2D SNV 12 49433083 G A P2763L 0 infinite n/an/a 3202 het PML52 MX1 SNV 21 42830468 G A R568H 0.00039 1 in n/a n/a3265 he 1 2,559 PML54 PARN SNV 16 14704607 G A R104C 0.000120 1 in n/an/a 3219 het 8,342 PML55 PLXNB1 SNV 3 48457498 G C L1004V 0 infinite n/an/a 3062 het PML55 FAT4 SNV 4 126412106 C G S2951C 0.037914 1 in 260.000400 1 in 2,501 3104 he PML55 FAT4 SNV 4 126412154 G A R2967K0.042189 1 in 24 0.000400 1 in 2,501 3105 het PML56 PRRC2A SNV 631603045 A G D1766G 0.001000 1 in n/a n/a 3133 hom 1,000 PML56 OAS3 SNV12 113405825 G A G155R 6.00E−05 1 in n/a n/a 3211 het 16,672 PML57 CD5SNV 11 60891358 C T R410C 0.000183 1 in n/a n/a 3182 het 5,475 PML57ITSN1 SNV 21 35122475 C T P125L 3.04E−05 1 in n/a n/a 3256 he 32,871PML58 MASP2 SNV 1 11106648 G A P126L 0.216611 1 in 5 see het see het3004 het SNV SNV PML58 MASP2 SNV 1 11106673 G A R118C 0 infinite 0infinite 3006 het PML59 CAMLG SNV 5 134076987 G C R136T 0 infinite n/an/a 3116 het PML60 RELA SNV 11 65423327 G A n/a 0.000300 1 in n/a n/a3184 het 3,337 PML62 KMT2D SNV 12 49421042 C T V4903M 0 infinite n/a n/a3199 het PML63 PLD1 SNV 3 171455697 G C P49A 0.033699 1 in 30 3.05E−04 1in 3,276 3069 het PML63 PLD1 SNV 3 171455739 A G F35L 0.011729 1 in 853.05E−04 1 in 3,276 3070 het PML64 MFN2 SNV 1 12049283 C T H20Y 0infinite n/a n/a 3007 het PML65 FAT4 SNV 4 126239421 C T R619C 0.0061171 in 163 0.000751 1 in 1,332 3084 het PML65 FAT4 SNV 4 126239986 C TA807V 0.325510 1 in 3 0.000751 1 in 1,332 3086 hom PML65 XAF1 SNV 176659427 C A N10K 0 infinite n/a n/a 3229 het PML66 MFN2 SNV 1 12064931 GA R481H 0 infinite n/a n/a 3009 het PML66 ADGRL2 SNV 1 82409337 A GQ228R 0.000192 1 in n/a n/a 3018 het 5,201 PML66 PLXNB1 SNV 3 48463544 GA P497L 0 infinite n/a n/a 3064 het PML66 MX1 SNV 21 42817460 C T P342L0 infinite n/a n/a 3264 het PML72 MX1 SNV 21 42812952 G A G221R 0infinite n/a n/a 3261 hetTable 34 lists potential cause(s) of PML in the study, SNVs (het, hom,or phased comp het) for genes in Table 31 with frequency <=1/1,000 ornovel.

TABLE 35 Case-solving Tier 2 SNVs (het, hom, or phased comp het) withfrequency <=1/1,00 but >1/1,000 Compound Variant Variant CompoundFrequency Frequency Frequency Frequency RefSeq Amino Details(Reciprocal, Details (Reciprocal, Sample Gene Variant Position Ref AltAcid (Ethnic Ethnic (Ethnic Ethnic SEQ ID Symbol Type Chromosome (hg19)Allele Allele Change specific) specific) specific) specific) IDMVGS1116- RNF125 SNV 18 29645930 A T R190S 0.004555 1 in 220 n/a n/a3237 8a het MVGS540- BLK SNV 8 11415492 A C K254T 0.004497 1 in 222 n/an/a 3163 374b het MVGS540- PRRC2A SNV 6 31604591 C T P2006S 0.282199 1in 4 0.002399 1 in 417 3134 393b het MVGS540- PRRC2A SNV 6 31604894 C TR2075W 0.034000 1 in 29 0.002399 1 in 417 3136 393b het MVGS811- PRRC2ASNV 6 31602967 G A R1740H 0.115236 1 in 9 see het see het 3132 13a homSNV SNV MVGS811- PRRC2A SNV 6 31605278 C T P2130L 0.045577 1 in 220.005004 1 in 200 3138 13a het PML01 PLK1 SNV 16 23693443 C T L21F0.006119 1 in 163 n/a n/a 3220 het PML02 PRRC2A SNV 6 31595926 C T P559S0.007481 1 in 134 n/a n/a 3122 het PML04 ADGRL2 SNV 1 82456165 G TG1130V 0.002578 1 in 388 n/a n/a 3021 het PML05 PRRC2A SNV 6 31595795 CT P515L 0.009777 1 in 102 0.001131 1 in 884 3121 het PML05 PRRC2A SNV 631602967 G A R1740H 0.149550 1 in 7 see het see het 3132 hom SNV SNVPML05 NOD1 SNV 7 30491693 C T R447H 0.006746 1 in 148 n/a n/a 3148 hetPML05 CD72 SNV 9 35612978 G A P234L 0.001558 1 in 642 n/a n/a 3171 homPML05 MON1B SNV 16 77225440 G T D20Y 0.009826 1 in 102 n/a n/a 3228 hetPML05 MX2 SNV 21 42752030 G A E177K 0.002074 1 in 482 n/a n/a 3258 hetPML09 MASP2 SNV 1 11090916 C A D371Y 0.655818 1 in 2 see het see het3002 hom SNV SNV PML09 MASP2 SNV 1 11106666 T C D120G 0.062380 1 in 160.004783 1 in 209 3005 het PML10 MASP2 SNV 1 11090916 C A D371Y 0.6558181 in 2 see het see het 3002 hom SNV SNV PML10 MASP2 SNV 1 11106666 T CD120G 0.062380 1 in 16 0.004783 1 in 209 3005 het PML10 MFN2 SNV 112064892 G A R468H 0.006444 1 in 155 n/a n/a 3008 het PML10 BLK SNV 811400849 C T P39L 0.006656 1 in 150 n/a n/a 3160 het PML10 RNF125 SNV 1829645930 A T R190S 0.004555 1 in 220 n/a n/a 3237 het PML13 ADGRL2 SNV 182416040 C T P323S 0.005425 1 in 184 n/a n/a 3019 het PML13 LRRK2 SNV 1240740686 A G N2081D 0.005082 1 in 197 n/a n/a 3198 het PML13 MMP9 SNV 2044640275 G A G296S 0.001154 1 in 867 n/a n/a 3254 het PML14 MBL2 SNV 1054531235 C T G54D 0.248456 1 in 4 0.008625 1 in 116 3175 het PML14 MBL2SNV 10 54531242 G A R52C 0.138866 1 in 7 0.008625 1 in 116 3176 hetPML15 CFHR2 SNV 1 196920123 G A R116Q 0.001567 1 in 638 n/a n/a 3030 hetPML16 RANBP2 SNV 2 109381493 G C A1500P 0.008681 1 in 115 n/a n/a 3046het PML16 PRRC2A SNV 6 31604610 T C V2012A 0.001126 1 in 888 n/a n/a3135 het PML16 AIRE SNV 21 45708278 G A G197R 0.002143 1 in 467 n/a n/a3268 het PML18 WASHC5 SNV 8 126095371 T C I106V 0.001990 1 in 502 n/an/a 3166 het PML19 SAMD9L SNV 7 92763720 G A A522V 0.006869 1 in 146 n/an/a 3154 het PML20 C8B SNV 1 57422511 C T E108K 0.002691 1 in 372 n/an/a 3016 hom PML20 HERCS SNV 4 89414196 G A G361R 0.003652 1 in 274 n/an/a 3072 het PML20 FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 20.004487 1 in 223 3086 het PML20 FAT4 SNV 4 126241785 G A V140710.036553 1 in 27 0.004400 1 in 223 3093 het PML20 PRRC2A SNV 6 31595795C T P515L 0.022579 1 in 44 0.002872 1 in 348 3121 het PML20 PRRC2A SNV 631602967 G A R1740H 0.258362 1 in 4 see het see het 3132 hom SNVs SNVsPML20 CCZ1 SNV 7 5959528 T C V203A 0.007045 1 in 142 n/a n/a 3146 hetPML22 C8A SNV 1 57378149 G T R485L 0.001712 1 in 584 n/a n/a 3013 homPML23 LRRK2 SNV 12 40657700 C G N299K 0.006768 1 in 148 n/a n/a 3192 homPML23 LRRK2 SNV 12 40702911 G A R1398H 0.006697 1 in 149 n/a n/a 3197hom PML26 FAT4 SNV 4 126239986 C T A807V 0.196043 1 in 5 see het see het3086 hom SNV SNV PML26 FAT4 SNV 4 126373570 C T S2098F 0.088450 1 in 110.010840 1 in 92 3099 het PML31 FAT4 SNV 4 126239986 C T A807V 0.3255101 in 3 see het see het 3086 hom SNV SNV PML3 FAT4 SNV 4 126389832 G AR2285Q 0.056972 1 in 18 0.006994 1 in 143 3100 het PML3 RABSB SNV 1256383856 A G I97V 0.003416 1 in 293 n/a n/a 3205 het PML31 FCER2 SNV 197754222 G A R274C 0.004261 1 in 235 n/a n/a 3241 het PML32 C3 SNV 196707129 G A R735W 0.006398 1 in 156 n/a n/a 3240 het PML33 BLK SNV 811412934 G A R167Q 0.008846 1 in 113 n/a n/a 3162 het PML36 CHD2 SNV 1593545488 T A S1407T 0.004813 1 in 208 n/a n/a 3216 het PML36 PLK1 SNV 1623700676 T A L463H 0.004422 1 in 226 n/a n/a 3221 het PML37 MASP2 SNV 111090287 C T D415N 0.036717 1 in 27 0.003304 1 in 303 3001 het PML37MASP2 SNV 1 11090916 C A D371Y 0.359923 1 in 3 0.003304 1 in 303 3002het PML37 MOGS SNV 2 74688884 G A R572W 0.008575 1 in 117 n/a n/a 3041hom PML37 FAT4 SNV 4 12639986 C T A807V 0.325510 1 in 3 see het see het3086 hom SNVs SNVs PML37 FAT4 SNV 4 126240377 G T K937N 0.021429 1 in 470.002630 1 in 380 3088 het PML37 FAT4 SNV 4 126408663 A G D2568G0.031611 1 in 32 0.003880 1 in 258 3101 het PML38 LRRK2 SNV 12 40702420A G I1371V 0.001055 1 in 948 n/a n/a 3195 het PML38 MMP9 SNV 20 44640275G A G296S 0.005222 1 in 191 n/a n/a 3254 het PML39 CFHR4 SNV 1 196871610A T R40* 0.005310 1 in 188 n/a n/a 3028 het PML39 CD36 SNV 7 80300449 TG Y249* 0.009686 1 in 103 n/a n/a 3150 hom PML39 NLRX1 SNV 11 119052975G T A843S 0.001182 1 in 846 n/a n/a 3188 hom PML39 ICAM1 SNV 19 10394724C T P218L 0.003194 1 in 313 n/a n/a 3242 het PML40 MLH1 SNV 3 37092025 CT H477Y 0.003985 1 in 251 n/a n/a 3060 het PML40 NOD1 SNV 7 30491693 C TR447H 0.006746 1 in 148 n/a n/a 3148 het PML40 TEK SNV 9 27183598 C TT2011 0.002950 1 in 339 n/a n/a 3169 het PML40 NLRX1 SNV 11 119052975 GT A843S 0.001734 1 in 577 n/a n/a 3188 het PML40 MX1 SNV 21 42815731 G AG293R 0.002418 1 in 414 n/a n/a 3263 het PML41 PLAU SNV 10 75675086 T CY314H 0.001730 1 in 578 n/a n/a 3179 het PML41 IFI35 SNV 17 41165632 G AR172Q 0.002886 1 in 347 n/a n/a 3232 het PML43 SERPINB2 SNV 18 61570402G A A371T 0.002162 1 in 463 n/a n/a 3239 het PML45 RAD50 SNV 5 131925413A G K307E 0.001430 1 in 700 n/a n/a 3114 het PML45 MX1 SNV 21 42807881 GA V75I 0.001409 1 in 710 n/a n/a 3260 het PML46 NLRX1 SNV 11 119045951 CT R547W 0.001904 1 in 525 n/a n/a 3187 het PML48 NFAT5 SNV 16 69725697 TG S563A 0.005437 1 in 184 n/a n/a 3227 het PML49 LRRK2 SNV 12 40677813 GT R793M 0.001409 1 in 710 n/a n/a 3194 hc PML51 TEK SNV 9 27197588 C TL444F 0.002243 1 in 446 n/a n/a 3170 het PML52 USB1 SNV 16 58054099 C GQ199E 0.007344 1 in 136 n/a n/a 3222 hom PML53 PRRC2A SNV 6 31599370 G CE974Q 0.002791 1 in 358 n/a n/a 3126 het PML54 RANBP2 SNV 2 109384800 CT T2602M 0.003726 1 in 268 n/a n/a 3048 het PML54 FAT4 SNV 4 126239986 CT A807V 0.196043 1 in 5 see het see het 3086 hom SNVs SNVs PML54 FAT4SNV 4 126372975 A C I1900L 0.022291 1 in 45 0.002732 1 in 366 3098 hetPML54 FAT4 SNV 4 126373570 C T S2098F 0.088450 1 in 11 0.010840 1 in 923099 het PML56 BLK SNV 8 11418856 C T R288C 0.002025 1 in 494 n/a n/a3164 het PML56 MSH5 SNV 6 31709045 C T L85F 0.001200 1 in 833 n/a n/a3139 hom PML56 MSH5 SNV 6 31729925 C T P108S 0.001409 1 in 710 n/a n/a3141 hom PML56 KMT2D SNV 2 49428694 T C D3419G 0.004830 1 in 207 n/a n/a3201 het PML61 CD22 SNV 19 35823528 C T A36V 0.002712 1 in 369 n/a n/a3248 het PML62 CFH SNV 1 196709774 G T E936D 0.004036 1 in 248 n/a n/a3024 hom PML63 FAT4 SNV 4 126239986 C T A807V 0.325510 1 in 3 see hetsee het 3086 hom SNV SNV PML63 FAT4 SNV 4 126389832 G A R2285Q 0.0569721 in 18 0.006994 1 in 143 3100 het PML63 ACD SNV 16 67694078 G T L102M0.002049 1 in 488 n/a n/a 3226 het PML63 AIRE SNV 21 45713696 G A G228R0.001432 1 in 698 n/a n/a 3269 het PML64 PLAU SNV 10 75672059 G A G41R0.001953 1 in 512 n/a n/a 3177 het PML66 HERC6 SNV 4 89352440 A C M709L0.002213 1 in 452 n/a n/a 3071 het PML68 RANBP2 SNV 2 109384800 C TT2602M 0.003726 1 in 268 n/a n/a 3048 het PML68 BLK SNV 8 11407690 C TR131W 0.001589 1 in 629 n/a n/a 3161 het PML72 CFHR2 SNV 1 196918732 G TR69L 0.007311 1 in 137 n/a n/a 3029 het PML72 CLEC16A SNV 16 11272435 GA S1017N 0.008537 1 in 117 n/a n/a 3218 hetTable 35 lists potential cause(s) of PML in the study, SNVs (het, hom,or phased comp het) for genes in Table 31 with frequency <1/1,00 but>/1,000.

TABLE 36 Case-solving un-phased potential comp het SNVs with comp hetfrequency <= 1/1,00 Predicted Compound Predicted Variant VariantCompound Frequency Frequency Frequency Frequency RefSeq Amino Details(Reciprocal, Details (Reciprocal, Sample Gene Variant Chromo- PositionRef Alt Acid (Ethnic Ethnic (Ethnic Ethnic SEQ ID Symbol Type some(hg19) Allele Allele Change specific) specific) specific) specific) IDMVGS1359 DNAJC21 SNV 5 34929974 A T E17V 0 infinite 0 infinite 3108 hetMVGS1359 DNAJC21 SNV 5 34937524 C T R178C 0 infinite 0 infinite 3109 hetMVGS1368 PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 2 0.005004 1 in200 3132 het MVGS1368 PRRC2A SNV 6 31605278 C T P2130L 0.045577 1 in 220.005004 1 in 200 3138 het MVGS540- PRRC2A SNV 6 31602967 G A R1740H0.439204 1 in 2 0.003733 1 in 268 3132 393b het MVGS540- PRRC2A SNV 631604894 C T R2075W 0.034000 1 in 29 0.003733 1 in 268 3136 393b hetMVGS540- CFTR SNV 7 117230454 G C G515A 0.015182 1 in 66 6.99E−05 1 in3155 393b het 14,314 MVGS540- CFTR SNV 7 117232223 C T R607C 0.018407 1in 54 6.99E−05 1 in 3157 393b het 14,314 MVGS811- LRRK2 SNV 12 40657700G G N299K 0.139067 1 in 7 2.09E−06 1 in 3192 13a het 479,386 MVGS811-LRRK2 SNV 12 40702910 C T R1398C 6.01E−05 1 in 2.09E−06 1 in 3196 13ahet 16,646 479,386 MVGS995- MSH5 SNV 6 31709045 C T L85F 0.041127 1 in24 0.000446 1 in 3139 4a het 2,242 MVGS995- MSH5 SNV 6 31729925 C TP108S 0.043373 1 in 23 0.000446 1 in 3141 4a het 2,242 PML01 FAT4 SNV 4126239986 C T A807V 0.490241 1 in 2 0.000273 1 in 3086 het 3,665 PML01FAT4 SNV 4 126241248 C G Q1228E 0.002227 1 in 449 0.000273 1 in 3091 het3,665 PML01 MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000310 1 in3139 het 3,224 PML01 MSH5 SNV 6 31725978 C G R188G 0.030171 1 in 33 seesee other 3140 het other het het SNVs SNVs PML01 MSH5 SNV 6 31729925 C TP108S 0.043373 1 in 23 0.000327 1 in 3141 het 3,057 PML02 PRRC2A SNV 631595926 C T P559S 0.007481 1 in 134 6.54E−05 1 in 3122 het 15,280 PML02PRRC2A SNV 6 31603045 A G D1766G 0.034995 1 in 29 6.54E−05 1 in 3133 het15,280 PML02 MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000446 1 in3139 het 2,242 PML02 MSH5 SNV 6 31729925 C T P108S 0.043373 1 in 230.000446 1 in 3141 het 2,242 PML04 FAT4 SNV 4 126237697 A C E44A0.000939 1 in see see other 3079 het 1,065 other het SNV het SNV PML04FAT4 SNV 4 126240968 A T E1134D 0.004166 1 in 240 see see other 3090 hetother het SNV het SNV PML04 FAT4 SNV 4 126411179 C T P2642L 0 infinite 0infinite 3102 het PML05 C8A SNV 1 57372463 C T T407I 0.003976 1 in 2521.15E−05 1 in 3011 he 86,659 PML05 C8A SNV 1 57373778 G A D458N 0.0116101 in 86 1.15E−05 1 in 3012 het 86,659 PML05 MOGS SNV 2 74688884 G AR572W 0.006223 1 in 161 0.000581 1 in 3041 het 1,720 PML05 MOGS SNV 274690378 C T D120N 0.373681 1 in 3 0.000581 1 in 3045 het 1,720 PML05CFTR SNV 7 117232086 G G561D 0 infinite 0 infinite 3156 het PML05 CFTRSNV 7 117246776 T C L925P 0 infinite 0 infinite 3158 het PML05 ERCC6L2SNV 9 98678698 G GC L202F 0.001389 1 in 720 0.000115 1 in 3172 het 8,675PML05 ERCC6L2 SNV 9 98691137 T C V403A 0.331883 1 in 3 0.000115 1 in3173 het 8,675 PML09 PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 20.002116 1 in 473 3132 het PML09 PRRC2A SNV 6 31605016 T C F2083S0.019275 1 in 52 see see other 3137 het other het het SNVs SNVs PML09PRRC2A SNV 6 31605278 C T P2130L 0.045577 1 in 22 0.000220 1 in 3138 het4,553 PML09 MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000446 1 in3139 het 2,242 PML09 MSH5 SNV 6 31729925 C T P108S 0.043373 1 in 230.000446 1 in 3141 het 2,242 PML10 FAT4 SNV 4 126239986 C T A807V0.490241 1 in 2 0.004647 1 in 215 3086 het PML10 FAT4 SNV 4 126412106 CG S2951C 0.037914 1 in 26 0.004647 1 in 215 3104 het PML10 PRRC2A SNV 631597469 A C K701Q 0.000186 1 in 1.62E−06 1 in 3124 het 5,385 615,476PML10 PRRC2A SNV 6 31603045 A G DI766G 0.034995 1 in 29 1.62E−06 1 in3133 het 615,476 PML10 MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 240.000446 1 in 3139 het 2,242 PML10 MSH5 SNV 6 31729925 C T P108S0.043373 1 in 23 0.000446 1 in 3141 het 2,242 PML15 SMARCAL1 SNV 2217285060 C G P165A 0.002972 1 in 337 1.58E−05 1 in 3050 het 63,333PML15 SMARCAL1 SNV 2 217288388 G C E241Q 0.021255 1 in 47 1.58E−05 1 in3052 he 63,333 PML15 TCN2 SNV 22 31006882 T G L30R 0.000691 1 in6.93E−06 1 in 3270 he 1,447 144,401 PML15 TCN2 SNV 22 31018975 T C L349S0.040090 1 in 25 6.93E−06 1 in 3272 het 144,401 PML16 FAT4 SNV 4126239986 C T A807V 0.491020 1 in 2 0.005173 1 in 193 3086 het PML16FAT4 SNV 4 126241720 C C L1385S 0.042138 1 in 24 0.005173 1 in 193 3092het PML16 PRRC2A SNV 6 31602967 G A R1740H 0.508843 1 in 2 0.000143 1 in3132 het 6,979 PML16 PRRC2A SNV 6 31604610 T C V2012A 0.001126 1 in 888see see other 3135 het other het het SNVs SNVs PML16 PRRC2A SNV 631605016 T C F2083S 0.013115 1 in 76 3.69E−05 1 in 3137 het 270,779PML16 PRRC2A SNV 6 31605278 C T P2130L 0.220930 1 in 5 6.22E−05 1 in3138 het 16,074 PML19 MOGS SNV 2 74689335 G T D421E 0.000817 1 in7.83E−05 1 in 3042 het 1,223 12,779 PML19 MOGS SNV 2 74690378 C T D120N0.382905 1 in 3 7.83E−05 1 in 3045 het 12,779 PML20 PLD1 SNV 3 171321023C T V1024I 0.036230 1 in 28 0.000305 1 in 3066 het 3,276 PML20 PLD1 SNV3 171455697 G C P49A 0.033699 1 in 30 0.000305 1 in 3069 het 3.276 PML20PRRC2A SNV 6 31595795 C T P515L 0.022579 1 in 44 0.0012 1 in 802 3121het PML20 PRRC2A SNV 6 31605278 C T P2130L 0.220930 1 in 5 0.001247 1 in802 3138 het PML21 PRRC2A SNV 6 31601735 G A R1563Q 0.087118 1 in 110.009566 1 in 105 3131 het PML21 PRRC2A SNV 6 31602967 G A R1740H0.439204 1 in 2 0.009566 1 in 105 3132 het PML25 NBAS SNV 2 15432775 C TR1518H 0.009143 1 in 109 0.000247 1 in 3033 het 4,053 PML25 NBAS SNV 215542352 C T R1004Q 0.107957 1 in 9 0.000247 1 in 3035 het 4,053 PML27LRRK2 SNV 12 40657700 C G N299K 0.139067 1 in 7 0.0048 1 in 206 3192 hetPML27 LRRK2 SNV 12 40702911 G A R1398H 0.139408 1 in 7 0.004847 1 in 2063197 het PML28 FAT4 SNV 4 126239623 G A S686N 5.99E−05 1 in see seeother 3085 het 16,684 other het het SNVs SNVs PML28 FAT4 SNV 4 126240255A G 1897V 3.00E−05 1 in 4.50E−10 1 in 3087 het 33,302 2,222,44 2,272PML28 FAT4 SNV 4 126240390 A G I942V 3.00E−05 1 in 4.50E−10 1 in 3089het 33,354 2,222,44 2,272 PML30 MOGS SNV 2 74690371 C T R122H 0 infinite0 infinite 3044 het PML30 MOGS SNV 2 74690378 C T D120N 0.236303 1 in 4see see other 3045 het other het SNV het SNV PML30 MSH5 SNV 6 31709045 CT L85F 0.041127 1 in 24 0.000446 1 in 3139 het 2,242 PML30 MSH5 SNV 631729925 C T P108S 0.043373 1 in 23 0.000446 1 in 3141 het 2,242 PML31PRRC2A SNV 6 31593603 A G Y265C 0 infinite 0 infinite 3120 het PML31PRRC2A SNV 6 31605278 C T P2130L 0.220930 1 in 5 see see other 3138 hetother het SNV het SNV PML33 PRRC2A SNV 6 31600558 C T R1370C 3.16E−05 1in see see other 3128 het 31,613 other het het SNVs SNVs PML33 PRRC2ASNV 6 31600696 G A G1416S 0.024081 1 in 42 1.90E−07 1 in 3129 het5,251,20 4 PML33 PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 23.47E−06 1 in 3132 het 287,912 PML33 PRRC2A SNV 6 31604591 C T P2006S0.282 1 in 4 2.23E−06 1 in 3134 het 199 448,095 PML36 C8A SNV 1 57333311C A A36E 0.002695 1 in 371 0.000233 1 in 3010 het 4,298 PML36 C8A SNV 157378149 G T R485L 0.345286 1 in 3 0.000233 1 in 3013 het 4,298 PML36FAT4 SNV 4 126238305 C A P247T 0.003905 1 in 256 0.000479 1 in 3081 het2,086 PML36 FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 2 0.000479 1 in3086 het 2,086 PML36 MSH5 SNV 6 31709045 C T L85F 0.136473 1 in 70.007228 1 in 138 3139 het PML36 MSH5 SNV 6 31729925 C T P108S 0.2118421 in 5 0.007228 1 in 138 3141 het PML38 MASP2 SNV 1 11090916 C A D371Y0.306713 1 in 3 0.004783 1 in 209 3002 het PML38 MASP2 SNV 1 11106666 TC D120G 0.062380 1 in 16 0.004783 1 in 209 3005 het PML38 PRRC2A SNV 631597451 G A A695T 0 infinite 0 infinite 3123 het PML38 PRRC2A SNV 631600696 G A G1416S 0.024081 1 in 42 see see other 3129 het other hetSNV het SNV PML38 RLTPR SNV 16 67680806 G A V181M 0.090170 1 in 110.000335 1 in 3223 het 2,989 PML38 RLTPR SNV 16 67685730 A D821V0.014840 1 in 67 0.000335 1 in 3224 het 2,989 PML39 MASP2 SNV 1 11094908T A D355V 0.017983 1 in 56 0.000974 1 in 3003 het 1,027 PML39 MASP2 SNV1 11106648 G A P126L 0.216611 1 in 5 0.000974 1 in 3004 het 1,027 PML39FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 2 0.003766 1 in 266 3086het PML39 FAT4 SNV 4 126336851 G A V2245I 0.030677 1 in 33 0.003766 1 in266 3096 het PML40 C8A SNV 1 57378149 G T R485L 0.161223 1 in 6 6.97E−061 in 3013 het 143,528 PML40 C8A SNV 1 57383295 G A G554D 0.000173 1 in6.97E−06 1 in 3014 het 5,785 143,528 PML40 MSH5 SNV 6 31709045 C T L85F0.090941 1 in 11 0.002240 1 in 446 3139 het PML40 MSH5 SNV 6 31729925 CT P108S 0.098531 1 in 10 0.002240 1 in 446 3141 het PML41 PRRC2A SNV 631602967 G A R1740H 0.508843 1 in 2 0.001668 1 in 599 3132 het PML41PRRC2A SNV 6 31605016 T C F2083S 0.013115 1 in 76 see see other 3137 hetother het het SNVs SNVs PML41 PRRC2A SNV 6 31605278 C T P2130L 0.2209301 in 5 0.000724 1 in 3138 het 1,381 PML41 TRAF3IP2 SNV 6 111913058 G AR78W 0.014991 1 in 67 0.000915 1 in 3144 het 1,093 PML41 TRAF3IP2 SNV 6111913262 C T D10N 0.244114 1 in 4 0.000915 1 in 3145 het 1,093 PML43PRRC2A SNV 6 31601735 G A R1563Q 0.087118 1 in 11 see see other 3131 hetother het het SNVs SNVs PML43 PRRC2A SNV 6 31602967 G A R1740H 0.4392041 in 2 0.009566 1 in 105 3132 het PML43 PRRC2A SNV 6 31604591 C T P2006S0.282199 1 in 4 0.006146 1 in 163 3134 het PML43 LRRK2 SNV 12 40657700 CG N299K 0.139067 1 in 7 0.004847 1 in 206 3192 het PML43 LRRK2 SNV 1240702911 G A R1398H 0.139408 1 in 7 0.004847 1 in 206 3197 het PML44 C8ASNV 1 57333311 C A A36E 0.015385 1 in 65 0.000327 1 in 3010 het 3,060PML44 C8A SNV 1 57378149 G T R485L 0.084963 1 in 12 0.000327 1 in 3013hct 3,060 PML44 PLD1 SNV 3 171379953 C T R708H 3.00E−05 1 in see seeother 3067 het 33,309 other het SNV het SNV PML44 PLD1 SNV 3 171431726 CG E290Q 0 infinite 0 infinite 3068 het PML44 FAT4 SNV 4 126239986 C TA807V 0.490241 1 in 2 0.005171 1 in 193 3086 het PML44 FAT4 SNV 4126412154 G A R2967K 0.042189 1 in 24 0.005171 1 in 193 3105 het PML46SAMD9 SNV 7 92732769 T C D881G 0.037350 1 in 27 0.001101 1 in 908 3151he PML46 SAMD9 SNV 7 92733766 C A V549L 0.117932 1 in 8 0.001101 1 in908 3152 het PML46 CFTR SNV 7 117230454 G C G515A 0.008531 1 in 1172.00E−05 1 in 3155 het 49,970 PML46 CFTR SNV 7 117232223 C T R607C0.009383 1 in 107 2.00E−05 1 in 3157 het 49,970 PML49 FAT4 SNV 4126239986 C T A807V 0.490241 1 in 2 0.010840 1 in 92 3086 het PML49 FAT4SNV 4 126373570 C T S2098F 0.088450 1 in 11 0.010840 1 in 92 3099 hetPML50 PRRC2A SNV 6 31601735 G A R1563Q 0.010692 1 in 94 see see other3131 het other het het SNVs SNVs PML50 PRRC2A SNV 6 31602967 G A R1740H0.508843 1 in 2 0.001360 1 in 735 3132 het PML50 PRRC2A SNV 6 31604591 CT P2006S 0.324640 1 in 3 0.000868 1 in 3134 het 1,152 PML51 PRRC2A SNV 631600696 G A G1416S 0.024081 1 in 42 see see other 3129 het other hethet SNVs SNVs PML51 PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 20.002644 1 in 378 3132 het PML51 PRRC2A SNV 6 31604591 C T P2006S0.282199 1 in 4 0.001699 1 in 589 3134 het PML55 FAT4 SNV 4 126239986 CT A807V 0.490241 1 in 2 see see other 3086 het other het het SNVs SNVsPML55 FAT4 SNV 4 126412106 C G S2951C 0.037914 1 in 26 0.004647 1 in 2153104 het PML55 FAT4 SNV 4 126412154 G A R2967K 0.042189 1 in 24 0.005171 in 193 3105 het PML55 SAMD9 SNV 7 92732769 T C D881G 0.046152 1 in 220.002109 1 in 474 3151 het PML55 SAMD9 SNV 7 92733766 C A V549L 0.1828321 in 5 0.0021 1 in 474 3152 het PML56 FAT4 SNV 4 126239986 C T A807V0.490241 1 in 2 0.005171 1 in 193 3086 het PML56 FAT4 SNV 4 126412154 GA R2967K 0.042189 1 in 24 0.005171 1 in 193 3105 het PML56 SAMD9 SNV 792732769 T C D881G 0.046152 1 in 22 0.002109 1 in 474 3151 het PML56SAMD9 SNV 7 92733766 C A V549L 0.182832 1 in 5 0.002109 1 in 474 3152het PML57 ITSN1 SNV 21 35122475 C T P125L 3.04E−05 1 in 1.01E−06 1 in3256 het 32,871 987,921 PML57 ITSN1 SNV 21 35239562 A G K102R 0.133092 1in 8 1.01E−06 1 in 3257 het 987,921 PML58 MASP2 SNV 1 11090916 C A D371Y0.359923 1 in 3 see see other 3002 het other het het SNVs SNVs PML58MASP2 SNV 1 11106648 G A P126L 0.216611 1 in 5 see see other 3004 hetother het het SNVs SNVs PML58 MASP2 SNV 1 11106673 G A R118C 0 infinite0 infinite 3006 het PML58 SMARCAL1 SNV 2 217285104 C G S179R 0.148576 1in 7 0.004848 1 in 206 3051 het PML58 SMARCAL1 SNV 2 217288388 G C E241Q0.130527 1 in 8 0.004848 1 in 206 3052 het PML58 FAT4 SNV 4 126238090 GT R175L 0.001241 1 in 806 0.000152 1 in 3080 he 6,565 PML58 FAT4 SNV 4126239986 C T A807V 0.491020 1 in 2 0.000152 1 in 3086 het 6,565 PML59MOGS SNV 2 74688563 C T G679S 0.091076 1 in 11 0.008718 1 in 115 3040het PML59 MOGS SNV 2 74690378 C T D120N 0.382905 1 in 3 0.008718 1 in115 3045 het PML59 PEPD SNV 19 33968991 T A E106V 0.096099 1 in 100.001747 1 in 572 3246 het PML59 PEPD SNV 19 33980963 G A R148C 0.0727321 in 14 0.001747 1 in 572 3247 het PML60 FAT4 SNV 4 126239241 G A V559I0 infinite 0 infinite 3082 het PML60 FAT4 SNV 4 126411493 C T P2747S 0infinite 0 infinite 3103 het PML61 C8A SNV 1 57372463 C T T407I 0.0871991 in 11 0.007527 1 in 133 3011 het PML61 C8A SNV 1 57378149 G T R485L0.345286 1 in 3 0.007527 1 in 133 3013 het PML63 C8A SNV 1 57372463 C TT4071 0.087199 1 in 11 0.007527 1 in 133 3011 het PML63 C8A SNV 157378149 G T R485L 0.345286 1 in 3 0.007527 1 in 133 3013 het PML63 PLD1SNV 3 171321023 C T V1024I 0.036230 1 in 28 see see other 3066 het otherhet het SNVs SNVs PML63 PLD1 SNV 3 171455697 G C P49A 0.033699 1 in 300.000305 1 in 3069 het 3,276 PML63 PLD1 SNV 3 171455739 A G F35L0.011729 1 in 85 0.000106 1 in 3070 het 9,413 PML63 PEPD SNV 19 33892731A G I118T 0.042743 1 in 23 see see other 3245 het other het het SNVsSNVs PML63 PEPD SNV 19 33968991 T A E106V 0.096099 1 in 10 0.001027 1 in974 3246 het PML63 PEPD SNV 19 33980963 G A R148C 0.072732 1 in 140.000777 1 in 3247 het 1,287 PML64 FAT4 SNV 4 126239986 C T A807V0.491020 1 in 2 0.001700 1 in 588 3086 het PML64 FAT4 SNV 4 126373570 CT S2098F 0.013846 1 in 72 0.001700 1 in 588 3099 het PML72 EGF SNV 4110866260 G C D257H 0.042672 1 in 23 0.000480 1 in 3075 het 2,084 PML72EGF SNV 4 110897252 C G S596R 0.044974 1 in 22 0.000480 1 in 3076 het2,084Table 36 lists potential cause(s) of PML in the study, un-phasedpotential comp bet SNVs for genes in Table 31 with frequency <=1/100.

TABLE 37 Gene burden genes (same criteria as Table 13) RefSeq Ave AveAve Ave Gene PML ExAC ExAC Ave FET corr Ave Ethnicity Symbol Cases CasesSamples FET (270) OR Ethnicity Overlap ORC4 8 247 33171 1.51E−094.08E−07 29.62 EUR PRRC2A 17 729 30571 1.54E−08 4.17E−06 27.58 EUR EUR +AFR PINK1 7 315 24054 1.79E−06 4.82E−04 14.26 EUR FAT4 23 6454 329742.16E−05 5.84E−03 4.64 EUR EUR + AFR LRRK2 9 1431 32539 7.96E−052.15E−02 6.41 EUR PLD1 12 257 5158 5.87E−11 1.58E−08 25.43 AFR PRRC2A 852 4536 3.27E−08 8.83E−06 57.80 AFR EUR + AFR FAT4 16 1259 4867 5.64E−061.52E−03 9.14 AFR EUR + AFR CTC1 6 159 4730 5.64E−05 1.52E−02 11.50 AFRTable 37 lists genes in Table 31 for which the total burden of damagingvariants (heterozygous) was found to be statistically greater in PMLcases versus ExAC controls. As was observed in gene burden analysisperformed on the original set of 435 genes, only the category ofheterozygous damaging variants yielded significant genes for the new setof 270 immune dysregulation genes.

TABLE 38 Variant burden Tier 1 SNVs (same criteria as Table 14) RefSeqGene Variant PML PML PML ExAC ExAC ExAC Symbol (hg19) Genotype EUR 44AFR 21 LAT 5 EUR AFR LAT CFHR3 chr1: 196759282, hom 3 3 0 57/ 41/ 16/C > T 28,802 2,986 4,514 FAT4 chr4: 126412634, het 0 4 0 76/ 176/ 19/C > G 33,339 5,194 5,784 PLAU chr10: 75673748, hom 0 3 0 0/ 141/ 0/ A >C 33,321 5,198 5,780 MDC1 chr6: 30675830, het 1 4 1 711/ 118/ 148/ T > A31,685 4,585 5,730 MDC1 chr6: 30680721, het 1 4 1 712/ 125/ 148/ G > A31,652 4,581 5,730 RAB5B chr12: 56385915, het 0 3 0 189/ 26/ 35/ GGGA >G 33,331 5,198 5,779 CCBE1 chr18: 57103126. het 2 3 0 768/ 21/ 83/ G > A33,368 5,201 5,789 PLD1 chr3: 171321023, het 0 3 0 101/ 188/ 20/ C > T33,301 5,189 5,742 MYSM1 chr1: 59131311, het 16 7 0 7,209/ 1,248/ 645/G > T 33,225 4,889 5,765 TCN2 chr22: 31008867, het 6 0 0 1,216/ 41/ 69/T > C 33,109 5,144 5,776 MOGS chr2: 74690378, het 17 10 1 7,884/ 1,877/2,161/ C > T 33,364 4,902 5,783 WRAP53 chr17: 7592168, het 15 8 2 6,828/1,712/ 1,880/ C > G 33,192 5,136 5,783 MOGS chr2: 74690039, het 17 9 18,286/ 1,610/ 2,178/ G > A 33,133 4,889 5,776 OAS2 chr12: 113448288, het26 8 1 14,781/ 560/ 1,544/ A > G 33,329 5,190 5,784 TMC8 chr17:76130947, het 7 9 0 5,032/ 848/ 492/ G > T 33,022 5,148 5,758 NBAS chr2:15674686, hom 25 8 2 15,155/ 406/ 1,556/ T > C 33,366 5,202 5,786 NBASchr2: 15607842, hom 25 7 2 15,009/ 221/ 1,491/ T > C 32,894 5,133 5,637SERPINA1 chr14: 94847262, het 6 1 0 1,942/ 81/ 253/ T > A 33,369 5,2035,789 FAT4 chr4: 126412154, het 5 0 0 1,407/ 99/ 112/ G > A 33,350 5,1925,785 NCF4 chr22: 37271882, het 17 5 0 9,101/ 522/ 1,402/ T > C 33,3665,202 5,788 MMP9 chr20: 44640959, hom 18 5 0 10,856/ 329/ 410/ G > A32,887 4,800 5,748 CTC1 chr17: 8138569, het 0 4 0 1,235/ 42/ 92/ C > G32,722 4,721 5,747 OAS1 chr12: 113357237, het 22 6 3 14,796/ 648/ 1,548/G > C 33,345 5,201 5,784 OAS1 chr12: 113357209, het 22 6 3 14,788/ 648/1,548/ G > A 33,270 5,201 5,780 CD5 chr11: 60893235, hom 15 10 0 9,028/1,386/ 3,098/ C > T 33,233 5,189 5,770 OAS1 chr12: 113357442, het 22 6 313,136/ 594/ 1,355/ G > A 28,065 4,740 4,892 C7 chr5: 40964852, het 16 90 12,068/ 552/ 1,966/ A > C 33,346 4,899 5,755 SRP54 chr14: 35497285,het 14 5 0 9,945/ 391/ 887/ T > C 33,265 5,189 5,776 NLRP2 chr19:55494157, het 9 0 0 2,739/ 1,241/ 1,774/ G > A 33,004 5,094 5,706 RefSeqGene PML PML PML PML PML PML Symbol EUR OR EUR FET AFR OR AFR FET ALL ORALL FET CFHR3 36.90 0.000107 11.97 0.003235 29.76 1.250E−07 FAT4 NA NA6.71 0.005182 9.85 0.000959 PLAU NA NA 5.98 0.019009 14.02 0.001563 MDC11.01 1.000000 8.91 0.001977 3.94 0.005909 MDC1 1.01 1.000000 8.390.002435 3.90 0.006166 RAB5B NA NA 33.15 0.000192 7.89 0.007567 CCBE12.02 0.269436 41.11 0.000107 3.84 0.012489 PLD1 NA NA 4.43 0.039674 6.360.013380 MYSM1 2.06 0.026498 1.46 0.451989 1.87 0.017528 TCN2 4.140.005279 NA NA 3.02 0.019108 MOGS 2.03 0.031024 1.47 0.378471 1.800.021224 WRAP53 2.00 0.037960 1.23 0.647415 1.80 0.023425 MOGS 1.890.053205 1.53 0.356038 1.65 0.044663 OAS2 1.81 0.067220 5.09 0.0010601.62 0.048285 TMC8 1.05 0.834739 3.80 0.004015 1.75 0.059738 NBAS 1.580.132924 7.27 0.000118 1.59 0.064503 NBAS 1.57 0.172287 11.11 2.070E−051.52 0.085087 SERPINA1 2.56 0.041248 3.16 0.283151 2.05 0.092465 FAT42.91 0.037262 NA NA 2.03 0.112929 NCF4 1.68 0.092908 2.80 0.053500 1.390.213191 MMP9 1.40 0.265273 4.25 0.012513 1.34 0.278668 CTC1 NA NA 26.214.110E−05 1.85 0.286669 OAS1 1.25 0.452928 2.81 0.039148 1.28 0.325931OAS1 1.25 0.544210 2.81 0.039148 1.28 0.326337 CD5 1.39 0.310432 2.490.044954 1.26 0.364341 OAS1 1.14 0.762822 2.79 0.040180 1.19 0.466504 C71.01 1.000000 5.91 0.000253 1.12 0.703241 SRP54 1.09 0.744651 3.830.018196 1.10 0.783330 NLRP2 2.84 0.009214 NA NA 0.98 1.000000Table 38 lists top tier of variants found to be significant on the basisof variant burden analysis for genes in Table 31.

TABLE 39 Variant burden Tier 2 SNVs (same criteria as Table 15) RefSeqGene Variant PML PML PML ExAC ExAC ExAC Symbol (hg19) Genotype EUR 44AFR 21 LAT 5 EUR AFR LAT CLPB chr11: het 0 2 1 5/ 27/ 1/ 72145307,32,307 4,744 5,748 C > G NOD1 chr7: het 0 2 0 3/ 1/ 1/ 30491421, 33,1525,131 5,782 G > T MDC1 chr6: hct 2 1 0 32/ 7/ 7/ 30673403, 32,318 4,9735,692 A > G PLAUR chr19: het 4 0 0 295/ 8/ 41/ 44153248, 33,361 5,2005,787 T > C PLEKHM1 chr17: hom 4 1 1 735/ 8/ 52/ 43555253, 30,909 4,4845,406 A > G TFPI chr2: het 0 2 0 2/ 63/ 2/ 188349523, 32,880 5,103 5,620A > G C8B chr1: het 2 2 0 408/ 18/ 31/ 57409459, 33,367 5,203 5,788 C >A FAT4 chr4: het 2 0 0 74/ 3/ 7/ 126241248, 33,236 4,867 5,779 C > G C9chr5: het 2 0 0 85/ 4/ 5/ 39311336, 33,334 5,201 5,770 A > T TMC8 chr17:het 2 0 0 115/ 2/ 3/ 76129619, 33,116 5,174 5,778 C > T EGF chr4: het 20 0 109/ 2/ 10/ 110929301, 33,340 5,201 5,739 T > C ATG7 chr3: het 0 2 048/ 47/ 27/ 11402163, 33,370 5,203 5,789 G > A ACD chr16: het 2 0 0 111/10/ 7/ 67694044, 31,250 4,297 5,689 C > T ICAM1 chr19: het 2 0 0 146/ 0/14/ 10395141, 32,810 4,915 5,732 G > A ATG5 chr6: het 3 0 0 404/ 6/ 22/106740989, 33,200 5,111 5,751 T > C NCF2 chr1: het 3 0 0 390/ 13/ 48/183532364, 33,366 5,203 5,787 T > A MCM5 chr22: het 3 0 0 405/ 14/ 64/35806756, 33,370 5,203 5,789 G > A EGF chr4: het 2 0 1 20/ 506/ 25/110865044, 33,364 5,202 5,787 G > C EGF chr4: het 2 0 1 22/ 549/ 29/110864533, 33,276 5,149 5,777 C > T FAT4 chr4: het 0 2 0 266/ 6/ 19/126238090, 33,051 4,835 5,744 G > T EGF chr4: het 2 0 0 13/ 261/ 22/110932508, 33,325 5,185 5,767 C > A PRRC2A chr6: het 1 2 0 610/ 60/ 102/31605016, 31,648 4,575 5,730 T > C SAMD9 chr7: hom 0 2 0 371/ 87/ 30/92733766, 33,364 5,111 5,783 C > A RNF125 chr18: het 2 0 0 152/ 324/ 44/29645930, 33,368 5,203 5,789 A > T RefSeq Gene PML PMR PML PML PML PMLSymbol EUR OR EUR FET AFR OR AFR FET ALL OR ALL FET CLPB NA NA 18.390.006992 58.03 2.860E−05 NOD1 NA NA 540.00 4.740E−05 259.18 5.180E−05MDC1 48.04 0.000986 35.47 0.033172 41.79 7.190E−05 PLAUR 11.21 0.000644NA NA 7.75 0.002261 PLEKHM1 4.11 0.020571 27.98 0.041216 4.72 0.002518TFPI NA NA 8.42 0.028496 19.11 0.005543 C8B 3.85 0.101548 30.32 0.0028005.82 0.006119 FAT4 21.34 0.004576 NA NA 15.34 0.008383 C9 18.63 0.005917NA NA 13.83 0.010166 TMC8 13.67 0.010601 NA NA 10.77 0.016190 EGF 14.520.009462 NA NA 10.73 0.016294 ATG7 NA NA 11.55 0.016157 10.67 0.016487ACD 13.36 0.011075 NA NA 9.45 0.020647 ICAM1 10.65 0.016849 NA NA 7.960.028184 ATG5 5.94 0.016651 NA NA 4.52 0.032035 NCF2 6.19 0.014980 NA NA4.36 0.035082 MCM5 5.96 0.016535 NA NA 4.07 0.041554 EGF 79.39 0.000385NA NA 3.56 0.057209 EGF 71.98 0.000462 NA NA 3.25 0.070527 FAT4 NA NA84.72 0.000491 4.38 0.080399 EGF 122.02 0.000176 NA NA 4.37 0.080707PRRC2A 1.18 0.580000 7.92 0.031896 2.39 0.139143 SAMD9 NA NA 6.080.050453 2.64 0.181292 RNF125 10.41 0.017592 NA NA 2.48 0.198848Table 39 lists second tier of variants found to be significant on thebasis of variant burden analysis for genes in Table 31.

TABLE 40 Summary of the subset of genes found to harbor variants ofinterest in the 70 PML cases (from Tables 34-39) Table 35 Table 38 Table39 Table 34 SNV Table 36 Variant Variant SNV Frequency Un-phased Burden,Burden, Tables 34-36 Frequency (Het, Hom, SNV PML Cases PML Cases TotalCase (Het, Hom, Comp Het) Frequency Table 37 >=5 2-4 EUR RefSeq GeneLevel Comp Het) <= 1/100 to (Comp Het) Gene EUR and/or and/or 2 SymbolSolutions <=1/1,000 >1/1,000 <=1/100 Burden 3 AFR AFR ACD 1 1 AFR EURADGRL2 4 2 AFR 1 AFR, 1 EUR AIRE 3 1 EUR 2 AFR ATG5 0 EUR ATG7 3 3 EURAFR BLK 6 1 EUR 5 EUR BRD4 1 1 EUR C3 1 1 EUR C7 1 1 EUR AFR, EUR C8A 71 EUR 3 AFR, 1 EUR, 2 LAT C8B 1 1 AFR AFR, EUR C9 0 EUR CAMLG 1 1 AFRCCBE1 0 AFR, EUR CCZ1 1 1 AFR CD22 1 1 AFR CD36 1 1 AFR CD37 1 1 AFR CD51 1 EUR CD72 1 1 LAT CFH 1 1 AFR CFHR1 1 1 LAT CFHR2 2 1 AFR, 1 LATCFHR3 0 AFR, EUR CFHR4 1 1 AFR CFHR5 1 1 AFR CFTR 3 1 EUR, 2 LAT CHD2 11 AFR CLEC16A 2 1 EUR 1 AFR CLPB 0 AFR, EUR COPA 1 1 LAT CTC1 0 AFR AFRDNAJC21 1 1 EUR EGF 1 1 AFR EUR, LAT ERCC6L2 1 1 LAT FAT4 23 3 AFR, 4AFR, 5 AFR, AFR, EUR AFR, EUR AFR, EUR 4 EUR 2 EUR 9 EUR FCER2 1 1 AFRHERC5 1 1 AFR HERC6 1 1 AFR ICAM1 1 1 AFR EUR IFI35 1 1 AFR IFIT1 1 1EUR IFIT3 1 1 AFR IL4 1 1 EUR ITSN1 1 1 EUR 1 EUR KMT2D 6 1 AFR, 1 EUR 4EUR KRAS 2 2 EUR LRRK2 8 1 AFR, 1 AFR, 3 EUR EUR 1 EUR 3 EUR MASP2 7 2AFR 1 AFR, 2 AFR, 2 EUR 1 EUR MBL2 2 1 LAT 1 EUR MCM5 0 EUR MDC1 0 AFR,EUR, AFR, EUR LAT MFN2 3 2 AFR 1 EUR MLH1 3 1 AFR, 1 LAT 1 EUR MMP9 2 1AFR, AFR, EUR 1 EUR MOGS 5 1 AFR 2 AFR, AFR, EUR, 1 EUR, LAT 1 LAT MON1A1 1 EUR MON1B 1 1 LAT MSH2 2 1 EUR, 1 LAT MSH5 9 1 EUR 1 AFR, 6 EUR, 1LAT MX1 8 2 AFR, 1 EUR, 4 EUR 1 LAT MX2 1 1 LAT MYSM1 0 AFR, EUR NBAS 21 EUR 1 EUR AFR, EUR, LAT NCF1 1 1 EUR NCF2 0 EUR NCF4 0 AFR, EUR NFAT51 1 EUR NLRP2 0 EUR NLRX1 4 1 EUR 1 AFR, 2 LAT NOD1 2 2 LAT AFR OAS1 0AFR, EUR, LAT OAS2 0 AFR, EUR, LAT OAS3 2 2 EUR ORC4 0 EUR PARN 1 1 EURPEPD 2 2 AFR PINK1 0 EUR PLAU 2 2 AFR AFR PLAUR 0 EUR PLCG1 1 1 AFR PLD13 1 AFR 2 AFR, AFR AFR 1 EUR PLEKHM1 0 AFR, EUR, LAT PLK1 2 1 AFR, 1 EURPLXNB1 3 1 AFR, 2 EUR PRRC2A 22 2 AFR, 2 AFR, 5 AFR, AFR, EUR AFR, EUR 6EUR, 4 EUR, 10 EUR 1 LAT 1 LAT RAB5A 1 1 EUR RAB5B 1 1 AFR AFR RAD50 1 1EUR RANBP2 4 1 EUR 1 AFR, 2 EUR RELA 1 1 EUR RLTPR 1 1 EUR RNF125 3 1AFR 2 EUR EUR RPSA 1 1 EUR RSAD2 1 1 EUR SAMD9 3 2 EUR, AFR 1 LAT SAMD9L2 1 AFR 1 AFR SERPINA1 0 AFR, EUR SERPINB2 1 1 EUR SMARCAL1 2 1 AFR, 1LAT SMURF2 1 1 AFR SRP54 0 AFR, EUR TBC1D17 1 1 LAT TCN2 1 1 LAT EUR TEK3 1 EUR 1 EUR, 1 LAT TFP1 0 AFR TMC8 0 AFR, EUR EUR TP53AIP1 1 1 EURTRAF3IP2 1 AFR USB1 1 1 EUR USP3 1 1 EUR VEGFA 1 1 EUR WASHC5 2 1 EUR 1EUR WRAP53 0 AFR, EUR, LAT XAF1 1 1 AFRTable 40 lists a summary of the subset of 270 genes found to harborvariants of interest in the 70 PML cases.

Example 23—Protein-Protein Interaction Analysis

This example contains analysis of protein-protein interactions (e.g.,pathway analysis) for the two sets of PML candidate genes: PML-435(Tables 6, 25A, and 25B3) and PML-270 (Table 31).

An integrated list of top candidate PML genes was generated from thethree analysis methods used herein: 1) case-solving approach (e.g.,Tables 7-9 and 34-36); 2) gene burden analysis (e.g., Tables 13 and 37);and 3) variant burden analysis for top findings (e.g., tier 1, Tables 14and 38) and second tier findings (e.g., tier 2, Tables 15 and 39). Agene-scoring metric was applied (see Table 42 for results) asfollows: 1) case-solving, the total number of unique PML cases that arepotentially solved were summed up for each gene, 2) gene burden, thenumber of ethnicities that were found to be significant for a given geneare reported (e.g., if AFR and FUR cases were significant in theirrespective analyses, then the reported number is 2), 3) variant burden(tier 1 or tier 2), the number of ethnicities that were found to besignificant for a given variant are reported, and 4) gene score total,the sum of steps 1-3 (case-solving, gene burden, and variant burden)were summed up to yield the total score for a given gene wherein ahigher number is a stronger candidate gene (e.g., FAT4 was thetop-scoring gene with a gene score total of 29). A total of 255 genes(derived from Tables 6, 25A, 25B, and 31) were found to have variants ofinterest in the set of 70 PML cases for which WES and array CGH datawere obtained. A gene score of >3 was set as the cutoff for pathwayanalysis, which yielded the 74 genes that are reported in Table 42.

Pathway analysis was performed on the set of 74 genes reported in Table42 using the String database resource (Szklarczyk D et al. 2017, PMID27924014). Default settings were used except for the “minimum requiredinteraction score”, which was set to “high confidence” (the defaultsetting is “medium confidence”).

The String database analysis yielded three main interaction networks:

-   -   1) 24-gene network (the output is depicted in FIG. 14 and        annotated in Table 42): BLK, CARD11, CFTR, EGF, IFIH1, ITSN2,        MAVS, MMP9, MX1, NFKB1, NLRX1, NOD1, NOD2, OAS1, OAS2, PIK3CD,        PLAU, PLCG2, RNF125, SAMD9, TEK, TICAM1, TLR4, ZAP70;    -   2) 13-gene network: ATM, ATR, BLM, DCLRE1C, LRRK2, MDC1, MLH1,        MSH5, POLE, PRKDC, RANBP2, RNF168, RTEL1; and    -   3) 3-gene network: C7, C8A, C8B.

TABLE 42 Gene Variant Variant Gene RefSeq Gene Source Case- Gene BurdenBurden Score 24-Gene GO: GO: GO: GO: GO: GO: GO: GO: GO: Symbol (Table)Solving Burden Tier 1 Tier 2 Total Network 0002250 0045087 00069550002252 0002253 0042113 0032479 0030217 0006958 ADGRL2 31 4 4 AIRE 31 33 AP3B1 6 5 1 6 ATG7 31 3 1 4 X ATM 6 8 2 10 X ATR 6 3 1 4 BLK 31 6 6 XX X X X BLM 6 2 1 3 X C7 31 1 2 3 X X X X X X C8A 31 7 7 X X X X X X C8B31 1 2 3 X X X X X X CARD11 6 3 3 X X X X X CFTR 31 3 3 X CHD7 6 4 1 1 6X DCLRE1C 6 10 10 X DOCK8 25A, 11 2 13 25B EGF 31 1 2 3 X X X EPG5 6 121 13 FAT4 31 23 2 2 2 29 GFI1 6 4 2 6 HIVEP1 6 6 1 7 HIVEP2 6 2 2 4HIVEP3 6 3 3 IDO2 6 5 5 IFIH1 6 3 3 6 X X X X X X IGLL1 6 3 2 5 X ITSN26 2 2 4 X KMT2D 31 6 6 LRBA 6 1 1 2 4 LRRK2 31 8 1 9 LYST 6 4 1 1 6 X XMASP2 31 7 7 X X X X X X MAVS 6 2 2 4 X X X X X MDC1 31 3 2 5 MFN2 31 33 MLH1 31 3 3 X X X X MMP9 31 2 2 4 X MOGS 31 5 3 8 MSH5 31 9 9 MX1 31 88 X X X X NBAS 31 2 3 5 NFKB1 6 3 3 X X X X X NLRX1 31 4 4 X X X NOD1 312 1 3 X X X X NOD2 6 6 1 7 X X X X X OAS1 31 3 3 X X X X OAS2 31 3 3 X XX X PIK3CD 6 4 1 5 X X X X X X X X PKHD1 6 11 11 PLAU 31 2 1 3 X PLCG2 65 2 2 9 X X X X PLD1 31 3 1 1 5 PLEKHM1 31 3 3 PLXNB1 31 3 3 POLE 6 7 29 PRKDC 6 4 4 X X X X X PRRC2A 31 22 2 2 26 RAG1 25A, 4 4 X X X 25BRANBP2 31 4 4 RBFOX1 6 2 1 3 RNF125 31 3 1 4 X X X X RNF168 6 5 5 X X XX RTEL1 6 2 1 3 SAMD9 31 3 1 4 X SHARPIN 6 2 1 2 1 6 SKIV2L 6 3 3 STXBP26 3 1 4 X X TEK 31 3 3 X TICAM1 6 2 1 3 X X X X X TLR4 6 9 9 X X X X X XX X TNFRSF11A 6 10 10 X X TRPM2 6 5 5 WRAP53 31 3 3 ZAP70 6 3 3 X X X XX X

Table 42 contains the gene scoring results, genes found in the 24-genenetwork, plus the top 5 “Biological Process” gene ontology (GO) pathways(based on the “false discovery rate” values reported in the String dboutput) and representative additional GO pathways of interest. Columnheadings and GO results are reported below:

RefSeq Gene Symbol, reports genes from Tables 6, 25A, 25B, and 31 thathad a “Gene Score Total” of >=3.

Gene Source, reports the original source table(s) of immunedysregulation genes.

Case-Solving, reports the total number unique PML cases that arepotentially solved using the case-solving approach (described herein forTables 7-9 and 34-36).

Gene Burden, reports the number of ethnicities (AFR, EUR, and/or LAT)that were found with the gene burden method (described herein for Tables13 and 37).

Variant Burden Tier 1, reports the number of ethnicities (AFR, EUR,and/or LAT) that were found with the variant burden method (describedherein for Tables 14 and 38).

Variant Burden Tier 2, reports the number of ethnicities (AFR, EUR,and/or LAT) that were found with the variant burden method (describedherein for Tables 15 and 39).

Gene Score Total, reports the sum of Case-Solving, Gene Burden, VariantBurden Tier 1, and Variant Burden Tier 2 entries (described herein),wherein only genes with a score of >=3 were included.

24-Gene Network, identifies the genes (marked with an X) found in thelargest network from the String db analysis (described herein), see FIG.14 for a graphical depiction.

The next 9 column headings list the “pathway ID” GO identifier numbersand identify the genes (marked with an X) that were found in eachpathway from the total set of 74 genes in Table 42. Also listed below isthe GO “pathway description”, the “count in gene set” (number of genesfrom Table 42), and the “false discovery rate” (association value):

-   -   GO:0002250, adaptive immune response, 13 genes, 1.12e-10    -   GO:0045087, innate immune response, 23 genes, 1.35e-10    -   GO:0006955, immune response, 26 genes, 1.54e-10    -   GO:0002252, immune effector process, 16 genes, 2.70e-09    -   GO:0002253, activation of immune response, 16 genes, 2.70e-09    -   GO:0042113, B cell activation, 9 genes, 5.24e-07    -   GO:0032479, regulation of type I interferon production, 8 genes,        3.70e-06    -   GO:0030217, T cell differentiation, 7 genes, 6.65e-05    -   GO:0006958, complement activation, classical pathway, 4 genes,        6.10e-04

Example 24—Analysis of Deleterious/Protective Variants

The WES data on the 70 PML cases were also analyzed for variants thatoccur at a statistically significant rate among the 705 total (435 fromthe original analysis and 270 from the second analysis) genes that haveherein been identified as playing a role in immune dysregulation. Inthis analysis, “statistically significant” can be having an FET P-Value,after Bonferroni correction, of P <4.95E⁻⁶. Inclusion criteria includedany SNV showing statistical significance at in one or more ethnic group(European, African or Latino) or across all groups. Some of thesevariants may occur with high frequency among the 70 PML cases. Some ofthese variants may occur in patients with HIV, MS, or other diseases asdescribed herein, or any combination thereof. Observation of thesevariants in the 70 PML cases suggests that there may be a link betweenthese variants and PML. Table 43 lists statistically significantdeleterious variants (such as variant 18-60052034-A-C, SEQ ID No. 1287),observed in the 70 PML cases with WES data. Table 44 lists statisticallysignificant protective variants observed in the 70 PML cases with WESdata. Column headers: Variant; Gene; Total PML; Ethnicities; Diseases;FET P-Values: EUR; FET P-Values: AFR; FET P-Values: LAT; FET P-Values:ALL; Odds Ratios: EUR; Odds Ratios: AFR; Odds Ratios: LAT; Odds Ratios:ALL.

TABLE 43 Summary of statistically significant deleterious variants thathave been observed in the 70 PML cases with WES data PML Ethnic- FETP-Values Odds Ratios Variant Gene Total ities Diseases EUR AFR LAT AllEUR AFR LAT All 1-154600405-T-C ADAR 69 3 3 1.2E−28 2.3E−34 7.0E−091.4E−53 165.6 Inf Inf 359.5 1-154600394-T-C ADAR 4 2 1 2.4E−02 1.2E−071.0E+00 1.4E−09 45.1 Inf 0.0 352.0 1-154600411-A-C ADAR 65 3 3 1.7E−291.0E−35 9.7E−08 4.7E−53 72.3 1510.3 344.0 93.3 1-33476387-C-T AK2 70 3 31.6E−16 3.5E−07 8.4E−03 7.4E−26 Inf Inf Inf Inf 1-33476385-C-G AK2 70 33 6.4E−16 9.5E−07 1.1E−02 7.3E−25 Inf Inf Inf Inf 1-33476353-C-T AK2 703 3 6.7E−07 2.1E−03 1.7E−01 8.0E−11 Inf Inf Inf Inf 1-33476435-C-A AK240 3 2 2.7E−82 2.0E−25 3.6E−10  6.9E−118 Inf Inf Inf Inf 1-33475721-G-CAK2 67 3 3 2.1E−11 1.5E−06 5.2E−02 7.0E−18 22.9 29.8 Inf 25.01-33476404-T-G AK2 64 3 3 2.9E−14 1.6E−07 4.0E−02 2.4E−22 18.1 29.9 8.519.2 1-33476396-G-A AK2 64 3 3 7.9E−14 2.5E−07 4.3E−02 1.2E−21 17.4 28.88.2 18.5 1-33475687-C-G AK2 49 3 3 9.8E−15 2.2E−04 2.0E−02 6.9E−18 12.76.5 12.3 9.0 1-33476143-G-A AK2 24 3 3 9.9E−08 6.9E−02 6.0E−02 2.3E−086.6 3.5 10.7 5.2 19-2129067-A-G AP3D1 21 3 3 2.0E−25 8.2E−13 3.5E−022.7E−39 Inf Inf Inf Inf 22-39357634-A-G APOBEC3A 16 3 2 9.2E−09 4.5E−062.7E−02 5.9E−18 31.9 12.0 46.4 31.9 22-39358241-C-T APOBEC3A 17 3 21.0E−07 1.2E−02 8.2E−06 7.1E−12 10.2 7.0 162.2 11.3 11-108114883-T-C ATM9 2 1 1.0E+00 2.4E−01 4.0E−06 1.8E−05 0.0 1.9 208.8 6.8 6-31997129-G-CC4B 26 2 3 3.1E−08 4.1E−04 6.0E−01 4.4E−08 6.2 7.8 0.0 4.411-60891305-A-C CD5 31 3 3 3.7E−51 3.0E−20 1.1E−05 2.1E−76 4176.5 Inf1278.4 4457.8 1-160519815-C-CT CD84 31 3 3 4.8E−06 1.6E−02 1.3E−031.2E−10 4.6 3.0 27.4 5.3 2-174229756-A-G CDCA7 3 1 2 3.6E−06 1.6E−011.0E+00 8.5E−02 124.7 0.0 0.0 3.0 14-23588326-G-C CEBPE 17 3 2 1.4E−253.8E−09 5.2E−03 1.8E−37 Inf Inf Inf Inf 14-23588316-T-C CEBPE 9 2 22.9E−15 1.5E−05 1.0E+00 7.1E−20 Inf 199.6 0.0 1010.1 1-196642969-CT-CCFH 2 1 1 1.0E+00 1.0E+00 3.8E−06 3.3E−02 0.0 0.0 1726.0 7.21-196797357-A-G CFHR1 37 3 3 3.4E−10 3.0E−02 1.0E+00 7.2E−12 7.2 2.6 1.25.5 16-88710039-T-C CYBA 5 2 1 3.2E−02 4.0E−04 1.0E+00 1.5E−07 Inf Inf0.0 Inf 1-161518336-C-T FCGR3A 30 3 3 1.6E−06 2.8E−03 6.5E−01 2.2E−06 4.7 4.1 0.4 3.4 4-89400457-C-A HERC5 6 2 1 3.4E−08 4.1E−05 1.0E+00 6.0E−12167.2 Inf 0.0 195.2 4-89400460-T-A HERC5 6 2 1 1.8E−06 3.3E−04 1.0E+006.8E−09 55.9 197.4 0.0 52.3 1-42049542-G-A HIVEP3 6 2 1 1.0E+00 1.0E+003.0E−06 2.3E−03 0.0 0.9 228.1 4.8 1-42050364-G-T HIVEP3 6 2 1 1.0E+001.0E+00 2.9E−06 2.5E−03 0.0 0.9 234.9 4.7 21-45650009-T-TG ICOSLG 19 3 32.8E−17 3.8E−14 1.4E−03 1.2E−34 Inf Inf Inf Inf 21-45649595-T-C ICOSLG 92 2 2.6E−06 2.5E−03 1.0E+00 1.1E−08 23.1 Inf 0.0 24.2 21-45649580-A-GICOSLG 9 2 2 2.2E−06 1.9E−02 1.0E+00 2.7E−07 16.7 Inf 0.0 14.610-1061646-T-C IDI2 39 3 3 2.5E−67 1.1E−21 3.1E−03 4.0E−93 Inf Inf InfInf 10-1061650-C-G IDI2 40 3 3 6.5E−67 2.6E−20 8.1E−06 1.0E−94 Inf InfInf Inf 8-42128955-A-G IKBKB 5 2 3 2.5E−06 3.6E−01 1.0E+00 3.1E−06 Inf4.2 0.0 87.4 5-78610478-A-C JMY 10 3 1 8.4E−14 2.2E−07 2.4E−03 1.5E−22468.4 Inf 910.6 581.7 5-78610472-T-C JMY 12 3 3 5.4E−11 2.2E−09 1.6E−066.5E−23 127.6 Inf Inf 225.3 19-48613788-T-G LIG1 35 3 3 1.5E−31 1.9E−216.6E−05 8.3E−59 Inf 261.6 169.8 590.8 21-42775180-C-CT MX2 9 2 2 3.7E−185.9E−08 1.0E+00 3.7E−26 Inf Inf 0.0 Inf 11-119050352-T-C NLRX1 3 2 21.8E−06 4.2E−03 1.0E+00 4.2E−09 Inf Inf 0 Inf 11-119044844-C-T NLRX1 4 21 2.0E−06 1.5E−01 1.0E+00 6.0E−02 154.9 0.2 0.0 2.8 11-119044158-C-TNLRX1 4 2 1 1.6E−06 2.4E−01 1.0E+00 6.5E−02 166.3 0.2 0.0 2.811-119045300-T-G NLRX1 5 2 1 4.2E−06 2.0E−01 1.0E+00 4.8E−02 115.8 0.30.0 2.6 11-119045431-T-C NLRX1 4 2 1 1.4E−06 1.5E−01 1.0E+00 7.8E−02173.4 0.2 0.0 2.6 6-51503623-T-A PKHD1 21 3 3 2.9E−03 5.7E−08 1.6E−015.2E−06 2.8 28.4 7.2 3.7 17-43552812-A-G PLEKHM1 21 3 3 2.5E−09 2.5E−069.1E−02 5.3E−14 10.4 20.5 13.0 11.3 22-37622880-G-GT RAC2 22 3 3 5.0E−246.6E−01 4.4E−05 4.3E−12 283.4 0.7 90.6 8.4 8-145154824-A-C SHARPIN 3 1 12.7E−08 1.0E+00 1.0E+00 4.9E−08 1082.8 0.0 0.0 892.3 11-62655878-C-TSLC3A2 7 2 1 1.0E+00 5.4E−01 1.0E−06 3.4E−04 0.0 1.3 336.4 5.819-50394219-G-C TBC1D17 20 3 3 1.7E−14 1.3E−05 4.1E−02 1.2E−20 36.4 19.241.4 33.0 18-60052034-A-C TNFRSF11A 9 2 1 1.4E−20 2.4E−05 1.0E+001.7E−25 Inf Inf 0.0 Inf

TABLE 44 Summary of statistically significant protective variants thathave been observed in the 70 PML cases with WES data PML Ethnic- FETP-Values Odds Ratios Variant Gene Total ities Diseases EUR AFR LAT AllEUR AFR LAT All 1-154562624-CG-C ADAR 7 2 3 1.2E−37 3.8E−13 5.9E−082.6E−60 0.0 0.0 0.0 0.0 1-154562625-G-C ADAR 4 1 1  2.5E−120 1.3E−343.7E−14  3.1E−168 0.0 0.0 0.0 0.0 1-33476223-TAC-T AK2 58 3 3 1.0E−043.7E−04 2.1E−01 1.8E−08 0.1 0.1 0.2 0.1 1-33475967-G-A AK2 41 3 39.6E−20 3.1E−05 2.3E−02 2.2E−28 0.0 0.1 0.0 0.0 1-33478931-G-C AK2 1 1 18.9E−24 1.0E−08 1.5E−03 5.9E−35 0.0 0.0 0.0 0.0 1-33475982-C-A AK2 4 2 18.6E−46 3.8E−10 8.9E−06 1.1E−63 0.0 0.0 0.0 0.0 1-33478959-C-G AK2 1 1 18.6E−37 3.8E−13 1.2E−05 1.9E−55 0.0 0.0 0.0 0.0 9-100756891-C-CT ANP32B12 3 3 6.0E−18 2.0E−07 1.7E−01 7.7E−23 0.1 0.1 0.2 0.1 19-2129473-T-CAP3D1 3 2 1 3.1E−18 4.0E−03 3.8E−01 3.9E−23 0.0 0.0 0.3 0.019-2129474-C-G AP3D1 3 1 2 8.2E−17 4.0E−03 6.3E−02 3.6E−23 0.0 0.0 0.00.0 22-39387655-G-T APOBEC3B 20 3 3 1.2E−10 6.5E−03 2.1E−02 5.4E−16 0.10.3 0.1 0.1 9-119491277-C-T ASTN2 2 2 1 1.0E−09 1.0E+00 1.0E+00 1.3E−090.0 0.7 0.0 0.1 5-115167595-CT-C ATG12 17 2 3 9.2E−15 3.8E−11 1.7E−065.6E−22 0.1 0.0 0.0 0.1 3-142231081-G-A ATR 8 3 2 9.9E−20 5.5E−155.9E−07 7.6E−34 0.0 0.0 0.0 0.0 6-31994974-G-A C4B 8 2 2 8.3E−02 1.1E−063.4E−01 3.5E−04 0.5 0.1 0.0 0.3 6-31994782-C-T C4B 7 3 3 4.5E−06 5.0E−015.3E−01 1.9E−06 0.2 0.4 1.5 0.2 6-31997401-G-A C4B 8 2 3 1.2E−06 7.1E−014.3E−03 2.0E−11 0.2 0.5 0.0 0.1 6-31997321-C-T C4B 19 3 3 8.4E−211.2E−03 5.9E−02 1.9E−25 0.0 0.2 0.1 0.1 6-31994750-T-C C4B 3 2 1 2.3E−056.0E−07 5.2E−03 3.4E−11 0.1 0.1 0.0 0.1 6-31994742-A-G C4B 3 2 1 2.3E−056.8E−07 4.7E−03 3.1E−11 0.1 0.1 0.0 0.1 6-31997600-C-G C4B 27 3 34.8E−16 2.6E−06 2.7E−05 9.4E−27 0.1 0.1 0.0 0.1 6-31994723-G-A C4B 3 1 25.3E−09 1.6E−01 1.4E−03 7.1E−15 0.1 0.0 0.0 0.1 9-123762321-G-A C5 12 23 5.7E−11 7.1E−02 7.9E−03 6.2E−17 0.1 0.2 0.0 0.1 2-87012399-TA-T CD8A 11 1 1.6E−11 1.4E−04 1.4E−01 4.9E−18 0.0 0.0 0.0 0.0 2-174230974-G-TCDCA7 15 3 2 8.5E−37 3.7E−01 2.9E−05 9.0E−34 0.0 0.6 0.0 0.020-48808011-C-T CEBPB 41 3 3 2.4E−07 2.4E−01 5.1E−02 2.6E−10 0.2 0.6 0.10.2 22-42343091-G-A CENPM 36 3 3 7.6E−01 1.9E−06 5.6E−01 1.0E+00 1.1 0.10.7 1.0 16-1493491-T-G CLCN7 33 3 3 1.3E−07 1.0E+00 3.8E−03 4.2E−06 0.21.1 0.0 0.3 13-40252190-C-T COG6 25 3 3 4.7E−06 3.5E−01 1.6E−01 1.8E−070.2 0.6 0.3 0.3 13-40326284-CA-C COG6 22 3 3 7.9E−11 7.7E−05 3.0E−021.8E−18 0.1 0.1 0.1 0.1 9-399275-A-AC DOCK8 20 3 3 1.0E+00 2.3E−063.8E−01 2.1E−02 1.0 0.1 0.3 0.5 12-93247775-G- EEA1 47 3 3 5.8E−024.5E−01 4.2E−06 1.6E−04 0.5 0.7 0.0 0.4 GAT

5-137847084- ETF1 3 3 1 2.8E−09 8.0E−05 6.5E−01 1.7E−12 0.0 0.1 0.4 0.1CACACACAT-C 5-137847090-CAT-C ETF1 2 2 1 5.3E−12 3.8E−03 1.8E−01 4.3E−160.0 0.1 0.0 0.0 12-11903753-C-T ETV6 2 2 1 1.0E+00 4.2E−12 4.3E−022.0E−03 0.0 0.0 0.1 0.2 12-11903752-G-T ETV6 2 2 1 1.0E+00 2.6E−153.0E−02 5.7E−04 0.0 0.0 0.1 0.1 12-11903751-TGC-T ETV6 1 1 1 8.9E−147.6E−15 4.9E−04 1.0E−26 0.0 0.0 0.0 0.0 8-39842443-C- IDO2 12 2 23.2E−10 3.3E−02 9.6E−03 1.4E−14 0.1 0.3 0.0 0.1 CTTA

22-17590180-G-A IL17RA 19 3 2 1.3E−11 6.9E−04 4.0E−01 2.2E−11 0.1 0.23.0 0.2 1-82402364- LPHN2 10 3 3 5.3E−10 2.4E−02 1.0E+00 1.7E−11 0.1 0.30.6 0.1 TAATC-

6-74161762-G-T MB21D1 3 2 2 7.3E−07 1.4E−01 5.9E−01 8.8E−07 0.0 3.6 0.00.1 21-42775180-C-T MX2 30 3 3 4.2E−38 7.8E−18 1.1E−10 1.5E−62 0.0 0.00.0 0.0 1-59150941-G-A MYSM1 54 3 3 9.6E−13 1.5E−05 1.0E+00 2.5E−16 0.00.0 Inf 0.0 7-74197598-T-A NCF1 5 2 2 3.0E−26 2.1E−01 4.8E−04 2.3E−270.0 0.4 0.0 0.0 22-37268257-C-T NCF4 52 3 3 5.7E−07 1.0E+00 1.5E−015.2E−07 0.1 0.9 0.1 0.2 11-119050352-T- NLRX1 2 2 1 2.5E−02 6.6E−071.0E+00 2.4E−04 0.2 0.0 0.0 0.1 TGAACAGGCA CATGGAAGGCC 12-113376543-OAS3 29 3 3 2.2E−09 1.7E−18 5.3E−03 2.7E−17 0.2 0.0 0.1 0.1 C-CCAAAGGG1-9714543-A-ACCCC PIK3CD 18 3 3 2.3E−09 1.2E−09 5.7E−03 5.2E−12 0.1 0.00.1 0.2 1-9714544-A-AG PIK3CD 18 3 3 1.7E−09 1.8E−12 4.8E−03 2.7E−12 0.10.0 0.1 0.2 1-9714541-C-CCA PIK3CD 18 3 3 1.7E−09 3.6E−12 4.5E−032.3E−12 0.1 0.0 0.1 0.2 12-133195625-G-A POLE 56 3 3 6.2E−12 2.7E−031.7E−02 1.2E−15 0.0 0.1 0.0 0.0 3-53223286- PRKCD 12 2 2 4.6E−21 1.2E−081.7E−01 1.1E−27 0.0 0.1 0.0 0.1 GCTGGT-G 3-53223291-T-G PRKCD 57 3 31.0E−20 1.7E−03 1.0E+00 6.3E−18 0.0 0.1 Inf 0.0 2-128181234-GC-G PROC 103 2 1.1E−09 1.7E−02 1.0E+00 1.7E−11 0.0 0.0 0.0 0.0 12-56380689-T-CRAB5B 6 3 2 8.7E−18 1.5E−06 8.7E−03 2.5E−24 0.0 0.1 0.1 0.011-62638333-T-A SLC3A2 12 3 3 3.1E−06 1.5E−01 1.0E+00 3.9E−09 0.2 0.21.0 0.2 11-62638330-T-A SLC3A2 15 3 3 1.1E−09 3.3E−02 1.0E+00 7.2E−140.1 0.1 0.7 0.1 11-62638200-T-A SLC3A2 3 2 1 6.9E−08 4.9E−03 1.7E−013.0E−11 0.0 0.0 0.0 0.0 5-147504315-A-T SPINK5 41 3 3 1.9E−18 5.1E−074.3E−02 1.0E−24 0.0 0.0 0.0 0.0 4-26862782-C-G STIM2 19 3 3 9.1E−106.1E−03 3.4E−03 4.5E−17 0.1 0.2 0.0 0.1 4-26862754-C-T STIM2 18 3 31.2E−18 2.8E−07 2.8E−04 1.9E−32 0.1 0.1 0.0 0.0 19-7705236-C-CTG STXBP234 3 3 5.4E−01 7.7E−08 3.6E−01 8.1E−02 0.8 0.1 3.6 0.6 19-50394205-T-CTBC1D17 1 1 1 2.1E−08 4.4E−05 1.0E+00 3.9E−13 0.0 0.0 0.0 0.022-19754091-A-C TBX1 16 2 2 1.7E−07 7.6E−01 6.5E−05 7.9E−13 0.2 1.2 0.00.2 2-47277208-A-G TTC7A 2 2 1 1.4E−17 1.3E−23 2.7E−04 8.6E−32 0.0 0.00.0 0.0 9-132640726-T-G USP20 24 3 3 5.0E−06 1.0E+00 6.8E−01 2.2E−07 0.21.0 0.6 0.3 9-132632162-G-GC USP20 53 3 3 3.3E−12 3.0E−02 1.0E−041.3E−15 0.0 0.3 0.0 0.1 11-9595768-C-T WEE1 13 3 3 1.7E - 07 9.0E−055.8E−01 5.9E−11 0.1 0.1 0.5 0.1

indicates data missing or illegible when filed

Example 25—Description of Further Sequence Data

The sequence file 56969-701.601 ST25.txt contains genomic informationfor:

-   -   1. The genetic sequence information referenced in Example 4 (SEQ        IDs 1-2177);    -   2. SEQ ID 2200-2203 are the distinct CNV sequences for the CNVs        in Table 28A;    -   3. SEQ ID 2204-2215 are the full genomic extent of the        transcript sequences for the transcripts in Table 30;    -   4. SEQ ID 2300-2893 are the full genomic extent of the        transcript sequences for the transcripts in Table 32;    -   5. SEQ ID 3000-3274 are the sequence variants listed in Table        33;    -   6. SEQ ID 3275-3281 are the full genomic extent of the        transcript sequences for the transcripts in Table 49;    -   7. SEQ ID 3300-3351 are the sequence variants listed in Table        45A;    -   8. SEQ ID 3400-3467 are the sequence variants listed in Table        45B;    -   9. SEQ ID 3500-3526 are the sequence variants listed in Table        45C.

TABLE 45A SEQ ID 3300-3351, SNV list (Table 43) with SEQ ID numbersChromosome Position (hg19) Ref Allele Alt Allele SEQ ID 1 33475687 C G3310 1 33475721 G C 3307 1 33476143 G A 3311 1 33476353 C T 3305 133476385 C G 3304 1 33476387 C T 3303 1 33476396 G A 3309 1 33476404 T G3308 1 33476435 C A 3306 1 42049542 G A 3328 1 42050364 G T 3329 1154600394 T C 3301 1 154600405 T C 3300 1 154600411 A C 3302 1 160519815C CT 3318 1 161518336 C T 3325 1 196642969 CT C 3322 1 196797357 A G3323 2 174229756 A G 3319 4 89400457 C A 3326 4 89400460 T A 3327 578610472 T C 3337 5 78610478 A C 3336 6 31997129 G C 3316 6 51503623 T A3345 8 42128955 A G 3335 8 145154824 A C 3348 10 1061646 T C 3333 101061650 C G 3334 11 60891305 A C 3317 11 62655878 C T 3349 11 108114883T C 3315 11 119044158 C T 3342 11 119044844 C T 3341 11 119045300 T G3343 11 119045431 T C 3344 11 119050352 T C 3340 14 23588316 T C 3321 1423588326 G C 3320 16 88710039 T C 3324 17 43552812 A G 3346 18 60052034A C 3351 19 2129067 A G 3312 19 48613788 T G 3338 19 50394219 G C 335021 42775180 C CT 3339 21 45649580 A G 3332 21 45649595 T C 3331 2145650009 T TG 3330 22 37622880 G GT 3347 22 39357634 A G 3313 2239358241 C T 3314

TABLE 45B SEQ ID 3400-3467, SNV list (Table 44) with SEQ ID numbersChromo- Position Ref Alt SEQ some (hg19) Allele Allele ID 1 9714541 CCCA 3449 1 9714543 A ACCCC 3447 1 9714544 A AG 3448 1 33475967 G A 34031 33475982 C A 3405 1 33476223 TAC T 3402 1 33478931 G C 3404 1 33478959C G 3406 1 59150941 G A 3442 1 82402364 TAATC T 3439 1 154562624 CG C3400 1 154562625 G C 3401 2 47277208 A G 3464 2 87012399 TA T 3423 2128181234 GC G 3453 2 174230974 G T 3424 3 53223286 GCTGGT G 3451 353223291 T G 3452 3 142231081 G A 3413 4 26862754 C T 3460 4 26862782 CG 3459 5 115167595 CT C 3412 5 137847084 CACACACAT C 3432 5 137847090CAT C 3433 5 147504315 A T 3458 6 31994723 G A 3421 6 31994742 A G 34196 31994750 T C 3418 6 31994782 C T 3415 6 31994974 G A 3414 6 31997321 CT 3417 6 31997401 G A 3416 6 31997600 C G 3420 6 74161762 G T 3440 774197598 T A 3443 8 39842443 C CTTAT 3437 9 399275 A AC 3430 9 100756891C CT 3407 9 119491277 C T 3411 9 123762321 G A 3422 9 132632162 G GC3466 9 132640726 T G 3465 11 9595768 C T 3467 11 62638200 T A 3457 1162638330 T A 3456 11 62638333 T A 3455 11 119050352 T TGAACA 3445 GGCACATGGAAG GCC 12 11903751 TGC T 3436 12 11903752 G T 3435 12 11903753 C T3434 12 56380689 T C 3454 12 93247775 G GATA 3431 12 113376543 C CCAAAG3446 GG 12 133195625 G A 3450 13 40252190 C T 3428 13 40326284 CA C 342916 1493491 T G 3427 19 2129473 T C 3408 19 2129474 C G 3409 19 7705236 CCTG 3461 19 50394205 T C 3462 20 48808011 C T 3425 21 42775180 C T 344122 17590180 G A 3438 22 19754091 A C 3463 22 37268257 C T 3444 2239387655 G T 3410 22 42343091 G A 3426

TABLE 45C SEQ ID 3500-3526, SNV list (Table 50A) with SEQ ID numbersChromosome Position (hg19) Ref Allele Alt Allele SEQ ID 1 27699670 AG A3500 1 42047208 C G 3501 1 57409459 C A 3502 1 92946625 G C 3503 1160769595 AG A 3504 1 196918605 A G 3505 2 163136505 C G 3506 2230579019 G A 3507 3 58191230 G T 3508 4 151793903 T C 3509 6 3015818 GA 3510 6 30673359 T G 3511 6 32814942 C T 3512 6 32816772 C A 3513 651798908 C T 3514 9 137779251 G A 3515 11 67818269 G A 3516 11 108106443T A 3517 14 94847262 T A 3518 16 81942175 A G 3519 19 7712287 G C 352019 8564523 T G 3521 19 48643270 C T 3522 21 45708278 G A 3523 2223915583 T C 3524 22 23915745 G A 3525 22 35806756 G A 3526

TABLE 48 GN 763-765, NCBI Gene ID, descriptions, RefSeq summary for 3genes from all-genes variant burden analyses (Table 50A) RefSeq NCBIGene Gene Gene Gene No. Symbol ID Description RefSeq Summmary (GN) FCN22220 ficolin-2 The product of this gene belongs to the ficolin family763 isoform a of proteins. This family is characterized by the precursorpresence of a leader peptide, a short N-terminal segment, followed by acollagen-like region, and a C- terminal fibrinogen-like domain. Thisgene is predominantly expressed in the liver, and has been shown to havecarbohydrate binding and opsonic activities. Alternatively splicedtranscript variants encoding different isoforms have been identified.[provided by RefSeq, July 2008]. LY9 4063 T-lymphocyte LY9 belongs tothe SLAM family of 764 surface antigen immunomodulatory receptors (seeSLAMF1; MIM Ly-9 isoform a 603492) and interacts with the adaptormolecule SAP precursor (SH2DIA; MIM 300490) (Graham et al., 2006 [PubMed16365421]).[supplied by OMIM, March 2008]. PRAM1 84106 PML-RARA- Theprotein encoded by this gene is similar to FYN 765 regulated bindingprotein (FYB/SLAP-130), an adaptor protein adapter involved in T cellreceptor mediated signaling. This molecule 1 gene is expressed andregulated during normal myelopoiesis. The expression of this gene isinduced by retinoic acid and is inhibited by the expression ofPML-RARalpha, a fusion protein of promyelocytic leukemia (PML) and theretinoic acid receptor-alpha (RARalpha). [provided by RefSeq, July2008].

TABLE 49 SEQ ID 3275-3281, non-redundant list of transcript variantsthat correspond to the genes in Table 48 RefSeq Gene RefSeq AccessionSEQ Symbol Number mRNA Description ID LY9 NM 001033667 Homo sapienslymphocyte antigen 9 (LY9), transcript 3275 variant 2, mRNA. LY9 NM001261456 Homo sapiens lymphocyte antigen 9 (LY9), transcript 3276variant 3, mRNA. LY9 NM 001261457 Homo sapiens lymphocyte antigen 9(LY9), transcript 3277 variant 4, mRNA. LY9 NM 002348 Homo sapienslymphocyte antigen 9 (LY9), transcript 3278 variant 1, mRNA. FCN2 NM004108 Homo sapiens ficolin (collagen/fibrinogen domain 3279 containinglectin) 2 (hucolin) (FCN2), transcript variant SV0, mRNA. FCN2 NM 015837Homo sapiens ficolin (collagen/fibrinogen domain 3280 containing lectin)2 (hucolin) (FCN2), transcript variant SV1, mRNA. PRAM1 NM 032152 Homosapiens PML-RARA regulated adaptor 3281 molecule 1 (PRAM1), mRNA.

Example 26—PML Discovery and Replication Cohorts

The cohort of 70 PML cases whose analysis was described previously(e.g., the genetic results reported in Table 7) can be considered a‘Discovery’ (Dis) cohort. An additional study was performed on a‘Replication’ (Rep) cohort comprising 115 additional PML cases. These115 cases were obtained from 4 different sources, only one of which wasthe same as one of the sources for the Dis cohort. Table 46 listsinformation for all 185 PML cases (Dis cohort=70 cases, Rep cohort=115cases). As was done for the Dis PML cohort (Example 3), WES data wasobtained on the 115 Rep PML cases. Unlike the Dis cohort, aCGH was notperformed on the Rep cohort. However, those skilled in the art know thatCNVs (e.g., those reported in Tables 1 and 28A) can be detected by othermethods besides aCGH. For example, the recurrent CNVS reported in Table1 and/or Table 28A can, at some stage, be easily screened for in the Repcohort using PCR-based methods (e.g., junction fragment PCR assays).

To confirm the ancestry of each PML case, which was reported by theclinician, WGS data (Gencove, NY, USA) was generated on genomic DNA forall 185 cases. The Gencove platform uses low pass sequencing at a readdepth of 0.1× that yields sufficient data (on the basis of SNPs) toascertain ethnicity and “uniqueness” of a sample. This data enableddetermination of:

-   -   A. Actual ethnicity, as opposed to relying on the        clinician-reported ethnicity;    -   B. Whether any of the 185 PML samples were duplicates. Because        PML is a rare disorder, it is possible that affected individuals        may have been seen multiple times by different medical centers.        None of the 185 samples were found to be duplicates.        Gencove reports the following categories of        ancestries/ethnicities (full name is following by abbreviation        used in parentheses): Americas (AMERICAS), Ashkenazi Jewish        (ASHKENAZI), Bengal (BENGALI), Central Africa (CAFRICA), Central        Asia (CASIA), Eastern Africa (EAFRICA), East Asia (EASIA),        Eastern Mediterranean (EMED), Finland (FINLAND), Central Indian        subcontinent (INDPAK), Northern Africa (NAFRICA), North-central        Asia (NCASIA), Middle East (NEAREAST), Northeast Asia (NEASIA),        Northeast Europe (NEEUROPE), Northern and Central Europe        (NEUROPE), Northern Italy (NITALY), Northern British Isles        (NNEUROPE), Oceania (OCEANIA), Southern Africa (SAFRICA),        Scandinavia (SCANDINAVIA), Southeast Asia (SEASIA), Southern        Indian subcontinent (SSASIA), Southwestern Europe (SWEUROPE),        Anatolia, Caucasus, Iranian Plateau (TURK-IRAN-CAUCASUS), and        Western Africa (WAFRICA). To simplify interpretation of the PML        patient variants using public databases, such as gnomAD and the        1000 genomes project (TGP), Gencove ethnicities were combined to        determine the highest percentage ethnicity for either European        ancestry (corresponding to NFE in gnomAD and EUR in TGP) or        African ancestry (corresponding to AFR in gnomAD and in TGP).        The following Gencove ethnicities were combined:        NFE/EUR=(EMED+NEEUROPE+NEUROPE+NITALY+NNEUROPE+SCANDINAVIA+SWEUROPE)        and AFR=(CAFRICA+EAFRICA+NAFRICA+SAFRICA+WAFRICA). The majority        of PML patients could be readily assigned as NFE/EUR or AFR        ethnicity, but a few individuals were binned according to their        closest ethnicity (e.g., patients with predominantly ASHKENAZI        and TURK-IRAN-CAUCASUS ancestry were assigned as NFE/EUR).

TABLE 46 Complete list of 185 PML cases in the Discovery (n = 70) andReplication (n = 115) cohorts aCGH Primary Primary Cohort Sample IDGender Expt ID Disease Ethnicity Dis MVGS1116-8a F 3006 MS NFE DisMVGS1359 F 3117 MS NFE Dis MVGS1368 F 3118 MS NFE Dis MVGS540-374b M3005 MS NFE Dis MVGS540-393b F 3004 MS NFE Dis MVGS694-6a F 3007 OtherNFE Dis MVGS811-13a M 3009 HIV AFR Dis MVGS995-4a M 3010 MS NFE Dis PMLIF 3127 HIV NFE Dis PML10 F 3157 HIV NFE Dis PML12 F 3159 HIV NFE DisPML13 M 3160 HIV NFE Dis PML14 M 3161 HIV NFE Dis PML15 M 3194 HIV AFRDis PML16 F 3163 HIV AFR Dis PML17 M 3140 HIV NFE Dis PML18 M 3141 HIVNFE Dis PML19 M 3164 HIV AFR Dis PML2 M 3126 Blood Cancers NFE Dis PML20M 3143 HIV AFR Dis PML21 M 3144 HIV NFE Dis PML22 M 3145 HIV NFE DisPML23 F 3165 HIV NFE Dis PML25 F 3166 HIV NFE Dis PML26 M 3167 HIV NFEDis PML27 M 3168 HIV NFE Dis PML28 F 3151 MS NFE Dis PML29 M 3152 HIVAFR Dis PML3 F 3155 MS NFE Dis PML30 M 3153 HIV NFE Dis PML31 F 3154 HIVAFR Dis PML32 M 3169 HIV NFE Dis PML33 M 3170 HIV NFE Dis PML35 F 3171HIV NFE Dis PML36 F 3172 HIV NFE Dis PML37 M 3173 HIV AFR Dis PML38 M3174 HIV NFE Dis PML39 M 3175 HIV AFR Dis PML4 M 3156 HIV NFE Dis PML40F 3273 HIV AFR Dis PML41 M 3177 HIV NFE Dis PML43 M 3178 HIV NFE DisPML44 M 3179 HIV NFE Dis PML45 F 3180 Blood Cancers NFE Dis PML46 M 3196HIV NFE Dis PML48 M 3197 Other NFE Dis PML49 M 3183 HIV NFE Dis PML5 M3125 HIV AFR Dis PML50 M 3198 HIV AFR Dis PML51 M 3185 HIV NFE Dis PML52F 3186 Blood Cancers NFE Dis PML53 M 3187 Other NFE Dis PML54 F 3188 HIVNFE Dis PML55 F 3189 HIV NFE Dis PML56 M 3190 HIV NFE Dis PML57 F 3191Blood Cancers NFE Dis PML58 M 3192 HIV AFR Dis PML59 M 3193 HIV AFR DisPML6 M 3124 HIV NFE Dis PML60 M 3199 HIV NFE Dis PML61 F 3200 HIV AFRDis PML62 F 3201 HIV AFR Dis PML63 M 3202 HIV AFR Dis PML64 M 3203 HIVAFR Dis PML65 M 3204 HIV AFR Dis PML66 M 3205 HIV AFR Dis PML68 F 3278MS NFE Dis PML69 M 3279 Other NFE Dis PML72 F 3282 HIV AFR Dis PML9 M3132 HIV NFE Rep PBPML100 F n/a Blood Cancers NFE Rep PBPML101 M n/aBlood Cancers NFE Rep PBPML102 F n/a Blood Cancers NFE Rep PBPML103 Mn/a Other NFE Rep PBPML104 F n/a Blood Cancers NFE Rep PBPML105 M n/aOther NFE Rep PBPML106 M n/a Other NFE Rep PBPML107 M n/a Blood CancersNFE Rep PBPML108 F n/a Blood Cancers NFE Rep PBPML109 M n/a BloodCancers NFE Rep PBPML110 M n/a HIV AFR Rep PBPML111 M n/a HIV AFR RepPBPML112 M n/a Blood Cancers NFE Rep PBPML113 M n/a HIV NFE Rep PBPML114M n/a Blood Cancers NFE Rep PBPML115 F n/a Other NFE Rep PBPML116 F n/aHIV NFE Rep PBPML117 M n/a HIV NFE Rep PBPML118 M n/a HIV NFE RepPBPML119 M n/a Other NFE Rep PBPML120 M n/a HIV NFE Rep PBPML121 M n/aHIV NFE Rep PBPML122 M n/a HIV NFE Rep PBPML123 F n/a MS NFE RepPBPML124 M n/a Other NFE Rep PBPML125 M n/a MS NFE Rep PBPML126 M n/aOther NFE Rep PBPML127 F n/a Other NFE Rep PBPML128 M n/a HIV AFR RepPBPML129 F n/a HIV AFR Rep PBPML130 M n/a Blood Cancers NFE Rep PBPML131M n/a HIV NFE Rep PBPML132 F n/a HIV AFR Rep PBPML133 M n/a HIV NFE RepPBPML134 F n/a HIV AFR Rep PBPML135 F n/a HIV NFE Rep PBPML136 F n/aOther NFE Rep PBPML137 M n/a HIV NFE Rep PBPML138 M n/a HIV NFE RepPBPML139 F n/a MS NFE Rep PBPML140 M n/a HIV NFE Rep PBPML141 M n/a HIVAFR Rep PBPML142 M n/a HIV NFE Rep PBPML143 M n/a HIV NFE Rep PBPML144 Fn/a HIV AFR Rep PBPML145 M n/a HIV NFE Rep PBPML146 M n/a Other NFE RepPBPML147 M n/a HIV NFE Rep PBPML148 M n/a HIV AFR Rep PBPML149 M n/aBlood Cancers NFE Rep PBPML150 M n/a HIV NFE Rep PBPML151 M n/a HIV AFRRep PBPML152 M n/a Other NFE Rep PBPML153 M n/a HIV NFE Rep PBPML154 Fn/a MS NFE Rep PBPML155 M n/a HIV NFE Rep PBPML156 F n/a Blood CancersNFE Rep PBPML157 M n/a HIV NFE Rep PBPML158 F n/a Other NFE Rep PBPML159M n/a HIV NFE Rep PBPML160 F n/a Blood Cancers NFE Rep PBPML161 F n/aHIV AFR Rep PBPML162 M n/a HIV NFE Rep PBPML163 F n/a Blood Cancers NFERep PBPML164 M n/a HIV NFE Rep PBPML165 F n/a HIV AFR Rep PBPML166 M n/aHIV NFE Rep PBPML167 M n/a HIV NFE Rep PBPML168 F n/a MS NFE RepPBPML169 M n/a HIV NFE Rep PBPML170 M n/a HIV AFR Rep PBPML171 M n/a HIVNFE Rep PBPML172 F n/a Blood Cancers NFE Rep PBPML173 M n/a Other NFERep PBPML174 M n/a Other NFE Rep PBPML175 F n/a HIV AFR Rep PBPML176 Fn/a Blood Cancers NFE Rep PBPML177 M n/a HIV NFE Rep PBPML178 M n/a HIVNFE Rep PBPML179 M n/a HIV NFE Rep PBPML180 F n/a HIV AFR Rep PBPML181 Mn/a HIV NFE Rep PBPML182 M n/a HIV NFE Rep PBPML183 M n/a HIV AFR RepPBPML184 F n/a HIV AFR Rep PBPML185 M n/a HIV NFE Rep PBPML186 F n/a HIVAFR Rep PBPML187 M n/a HIV NFE Rep PBPML188 M n/a HIV AFR Rep PBPML189 Fn/a HIV NFE Rep PBPML190 M n/a HIV AFR Rep PBPML191 F n/a HIV AFR RepPBPML77 M n/a HIV NFE Rep PBPML78 M n/a HIV NFE Rep PBPML79 F n/a HIVNFE Rep PBPML80 F n/a HIV AFR Rep PBPML81 M n/a HIV NFE Rep PBPML82 Fn/a HIV NFE Rep PBPML83 M n/a HIV AFR Rep PBPML84 M n/a HIV AFR RepPBPML85 F n/a HIV AFR Rep PBPML86 M n/a Other AFR Rep PBPML87 F n/a HIVNFE Rep PBPML88 M n/a Other NFE Rep PBPML89 M n/a HIV AFR Rep PBPML90 Mn/a HIV NFE Rep PBPML91 F n/a Blood Cancers NFE Rep PBPML92 F n/a HIVNFE Rep PBPML93 M n/a HIV AFR Rep PBPML94 M n/a Blood Cancers NFE RepPBPML95 F n/a MS NFE Rep PBPML96 F n/a HIV NFE Rep PBPML97 M n/a OtherNFE Rep PBPML98 M n/a Other NFE Rep PBPML99 F n/a Other NFETable 46 represents the complete set of PML patients in the Discovery(Dis) or Replication (Rep) cohorts. The Dis cohort is equivalent to thepatients listed in Table 7 except for PML67, for which insufficient DNAwas available to generate WES data. Table 46 also lists the Sample ID,Gender, aCGH Expt ID (also reported in Table 11), Primary Disease, andPrimary Ethnicity (based on Gencove ancestry analysis). Besides MS andHIV, the Primary Disease categories included Blood Cancers (mainlyleukemias and lymphomas) and Other (miscellaneous conditions such asanemia, lymphopenia, sarcoidosis, and transplant patients).

Example 27—Updated Sequence Analysis Pipeline

High-throughput sequencing and sequence analysis methods are continuallybeing developed to improve the quality of the data and results. A newapproach, complimenting the previous approach, was used for the analysisof the Dis and Rep cohort WES data. Google's DeepVariant (DV) caller(github.com/google/deepvariant) was used for variant calling (see Poplinet al. (2018) Nat Biotechnol. November; 36(10):983-987). Using GRCh37 asthe reference genome, BWA-aligned BAM files for each PML sample (Dis orRep cohort) was run through the DV caller. Variant inclusion criteriawere: DP >10 (site depths were calculated again directly from the BAMfiles, with constraints for Base Quality >10 and Mapping Quality >20,and DP <10 were treated as “NA”), VAF >0.2 for heterozygous calls (VAF<0.2 were treated as “NA”), and VAF >0.8 for homozygous calls (VAF<0.8_were treated as heterozygous calls). Annotation of DV-calledvariants was performed using dbNSFP (see Liu et al. (2016) Hum Mutat.2016 March; 37(3):235-41).

Variant burden analyses were performed using similar criteria as wasused for variants reported in Tables 14, 15, 38, and 39, except thatDV-called variants for the PML cases was used as input. The Dis and Repcohorts were analyzed separately, with separate output files beinggenerated for heterozygous (het) and homozygous (hom) variants. Forsimplicity, the genes listed in Tables 6, 25A, 25B, 26, and 31 werecombined into a non-redundant list of 705 genes. The 705-gene list wascompared to all genes that were found in the annotation reports for thetwo cohorts (Dis and Rep), which yielded a non-redundant gene list of663 genes that were used for the DV pipeline variant burden analyses. Inaddition to the 663-gene analyses, a parallel set of all-genes (all˜20,000 human genome genes) analyses were generated. To summarize, foreach variant observed, a total count was made of the number ofindividuals in the PML cohorts that possessed the variant, and this wassimilarly done for comparison in three different unselected populationcohorts: gnomAD exome (WES data), gnomAD genome (WGS data), and TGPexome (WES data). Fishers Exact Test (FET) and Odds Ratio (OR) werecalculated to identify statistically significant variants with thehighest OR values.

TABLE 47 663 genes analyzed for the 185 PML cases (DV pipeline) RefSeqIUIS-334 Gene Number Gene Symbol Gene Disease Model Cross-referencedtables (GN) ACADM no unknown Table 6 157 ACD no AD AR Table 31 493 ACKR1no AD AR Table 6 158 ACP5 yes AR Table 6 159 ACTB yes AD Table 31 494ACTN4 no unknown Table 31 495 ADA yes AR Table 25B; Table 26 1 ADA2 yesAR Table 31 496 ADAM17 yes AR Table 31 497 ADAR yes AD AR Table 6 160ADARB1 no unknown Table 6 2 ADGRL2 no unknown Table 31 498 ADK nounknown Table 6 161 AGBL4 no unknown Table 6 3 AICDA yes AD AR Table 6162 AIRE yes AD AR Table 31 499 AK2 yes AR Table 6 163 ALG12 no AR Table6 164 ALPL no unknown Table 6 165 ANP32B no unknown Table 31 500 APIS3yes AR Table 31 501 AP3B1 yes AR Table 6 166 AP3B2 no unknown Table 6167 AP3D1 yes AR Table 6 168 APOBEC3A no unknown Table 6 4 APOBEC3B nounknown Table 6 6 APOL1 yes unknown Table 6 169 ARHGEF7 no unknown Table6 8 ARPC1B yes AR Table 31 502 ASH1L no unknown Table 6 170 ASTN2 nounknown Table 6 9 ATG12 no unknown Table 31 503 ATG16L1 no unknown Table31 504 ATG5 no unknown Table 31 505 ATG7 no unknown Table 31 506 ATG9Ano unknown Table 31 507 ATL2 no unknown Table 6 171 ATM yes AR Table 6172 ATP6AP1 yes XLR Table 31 508 ATR no unknown Table 6 173 AUH nounknown Table 6 10 B2M yes AR Table 31 509 BACH1 no unknown Table 6 11BACH2 yes unknown Table 6 174 BAG3 no AR Table25A; Table 25B 175 BCL10yes AR Table 6 176 BCL11B yes AD Table 31 510 BCL2 no unknown Table 31511 BDKRB2 no unknown Table 6 12 BLK no AD Table 31 512 BLM yes AR Table6 177 BLNK yes AR Table 6 178 BLOC1S6 no AR Table 6 179 BMPR2 no unknownTable 6 13 BRD4 no unknown Table 31 513 BTK yes XLR Table25A; Table 25B180 BTLA no unknown Table 31 514 C11orf65 no unknown Table 6 181 C1QAyes AR Table 6 182 C1QB yes AR Table 6 183 C1QC yes AR Table 6 184 C1Ryes AR Table 31 515 C1S yes AR Table 31 516 C2 yes AR Table 31 517 C3yes AD AR Table 31 518 C4A yes AR Table 31 519 C4B yes AR Table 31 520C5 yes AR Table 31 521 C5AR1 no unknown Table 6 185 C6 yes AR Table 31522 C7 yes AR Table 31 523 C8A yes AR Table 31 524 C8B yes AR Table 31525 C8G yes AR Table 31 526 C9 yes AR Table 31 527 CAD no AR Table 31528 CAMLG no unknown Table 31 529 CAPZB no unknown Table 6 186 CARD11yes AD AR Table 6 187 CARD14 yes AD Table 31 530 CARD9 yes AR Table 6188 CASP10 yes AD Table 31 531 CASP8 yes AR Table 6 189 CAV1 no unknownTable 31 532 CCBE1 yes AR Table 31 533 CCDC22 no XLR Table 31 534 CCL11no unknown Table 6 190 CCL2 no unknown Table 6 191 CCL5 no unknown Table6 192 CCR2 no unknown Table 6 193 CCR5 no unknown Table 6 194 CCZ1 nounknown Table 31 535 CD180 no unknown Table 6 195 CD19 yes AR Table 6196 CD209 no unknown Table 6 197 CD22 no unknown Table 31 536 CD247 yesAR Table 6 198 CD27 yes AR Table 6 199 CD274 no unknown Table 31 537CD276 no unknown Table 31 538 CD300LF no unknown Table 6 23 CD34 nounknown Table 6 201 CD36 no AR Table 31 539 CD37 no unknown Table 31 540CD38 no unknown Table 31 541 CD3D yes AR Table 6 202 CD3E yes AR Table 6203 CD3G yes AR Table 6 204 CD40 yes AR Table 6 205 CD40LG yes XLRTable25A; Table 25B 206 CD46 yes AD Table 31 542 CD5 no unknown Table 31543 CD55 yes unknown Table 6 207 CD59 yes AR Table 6 208 CD70 yes ARTable 31 544 CD72 no unknown Table 31 545 CD74 no unknown Table 31 546CD79A yes AR Table 6 209 CD79B yes AR Table 6 210 CD81 yes AR Table 6211 CD84 no unknown Table 31 547 CD8A yes AR Table 6 212 CD93 no unknownTable 31 548 CDCA7 yes AR Table 6 213 CDKN1B no unknown Table 6 24 CEBPBno unknown Table 6 214 CEBPE yes AR Table 31 549 CENPM no unknown Table6 25 CFB yes AD AR Table 31 550 CFD yes AR Table 31 551 CFH yes AD ARTable 31 552 CFHR1 yes AD AR Table 31 553 CFHR2 yes AD AR Table 31 554CFHR3 yes AD AR Table 31 555 CFHR4 yes AD AR Table 31 556 CFHR5 yes ADAR Table 31 557 CFI yes AD AR Table 31 558 CFP yes XLR Table 31 559 CFTRyes AR Table 31 560 CHD2 no unknown Table 31 561 CHD7 yes AD Table 6 215CHEK1 no unknown Table 6 216 CIITA yes AR Table 6 217 CLCN7 yes AD Table6 218 CLEC16A no unknown Table 31 562 CLPB yes AR Table 31 563 COG4 nounknown Table 6 26 COG6 no AR Table 6 219 COMMD6 no unknown Table 6 27COPA yes AD Table 31 564 CORO1A yes AR Table 6 220 CR2 yes AR Table 6221 CRADD no unknown Table 6 28 CRTC3 no unknown Table 6 222 CSF2RA yesXLR Table 31 565 CSF2RB yes AR Table 31 566 CSF3R yes AR Table 6 223CTC1 yes AR Table 31 567 CTLA4 yes AD Table 6 224 CTPS1 yes AR Table 6225 CTSC yes AR Table 6 226 CX3CR1 no unknown Table 6 227 CXCL1 nounknown Table 31 568 CXCL10 no unknown Table 31 569 CXCL12 no unknownTable 6 228 CXCL5 no unknown Table 31 570 CXCL8 no unknown Table 31 571CXCL9 no unknown Table 6 229 CXCR1 no unknown Table 6 230 CXCR3 nounknown Table 31 572 CXCR4 yes AD Table 6 231 CXorf40A no unknown Table6 232 CYBA yes AR Table 31 573 CYBB yes XLR Table 6 233 CYP2S1 nounknown Table 6 234 DCLRE1B yes AR Table 31 574 DCLRE1C yes AR Table 6235 DDX1 no unknown Table 6 236 DDX58 yes AD Table 6 237 DHX58 nounknown Table 6 238 DKC1 yes XLR Table 6 239 DNAJC21 yes AR Table 31 575DNASE1L3 yes AR Table 31 576 DNASE2 yes AR Table 31 577 DNER no unknownTable 6 31 DNMT3B yes AR Table 25B 240 DOCK2 yes AR Table 6 241 DOCK8yes AR Table25A; Table 25B 242 DSC1 no unknown Table 6 243 DUSP16 nounknown Table 6 32 EBF1 no unknown Table 31 578 EDIL3 no unknown Table 634 EEA1 no unknown Table 6 35 EGF no unknown Table 31 579 EGR1 nounknown Table 6 244 EHF no unknown Table 6 36 ELANE yes AD Table 6 245EMB no unknown Table 6 37 EPG5 yes AR Table 6 246 ERCC6L2 yes AR Table31 580 ETF1 no unknown Table 6 247 ETV6 no AD Table 6 3: EXTL3 yes ARTable 31 581 F9 no unknown Table 6 248 FAAP24 yes AR Table 31 582 FADDyes AR Table 31 583 FAS yes AD Table 6 249 FASLG yes AD Table 6 250 FAT4yes AR Table 31 584 FCER2 no unknown Table 31 585 FCGR2A no AD AR Table6 251 FCGR3A yes AR Table 6 252 FCN3 yes AR Table 6 253 FERMT3 yes ARTable 31 586 FEZ1 no unknown Table 6 254 FHL2 no unknown Table 6 39 FIS1no unknown Table 31 587 FOS no unknown Table 6 255 FOXH1 no unknownTable 6 256 FOXN1 yes AR Table 6 257 FOXP3 yes XLR Table 6 258 FPR1 yesunknown Table 6 259 FPR2 no unknown Table 6 41 FPR3 no unknown Table 642 FUK no unknown Table 6 43 G6PC3 yes AR Table 6 260 G6PD yes XLD Table31 588 GATA2 yes AD Table 6 261 GDA no unknown Table 6 44 GDPD4 nounknown Table 6 45 GFI1 yes AD Table 6 262 GINS1 yes AR Table 31 589GOLGB1 no unknown Table 6 263 GPATCH2 no unknown Table 6 46 GPC5 nounknown Table 6 GPRCSA no unknown Table 6 264 GRAP2 no unknown Table 6265 GRIA3 no unknown Table 6 51 GTPBP4 no unknown Table 6 52 HAX1 yes ARTable 6 266 HCN1 no unknown Table 6 53 HELLS yes AR Table 6 267 HERC5 nounknown Table 31 590 HERC6 no unknown Table 31 591 HEXA no unknown Table6 54 HIVEP1 no unknown Table 6 268 HIVEP2 no AD Table 6 269 HIVEP3 nounknown Table 6 270 HK2 no unknown Table 6 55 HMGB1 no unknown Table 31592 HMOX1 yes AR Table 31 593 HNRNPLL no unknown Table 6 271 HP nounknown Table 6 272 HPCAL1 no unknown Table 6 273 HPR no unknown Table 65' HTR2A no unknown Table 6 274 HYOU1 yes AR Table 31 594 ICAM1 nounknown Table 31 595 ICOS yes AR Table 6 275 ICOSLG no unknown Table 31596 IDI1 no unknown Table 6 276 IDI2 no unknown Table 6 59 IDO2 nounknown Table 6 61 IFI35 no unknown Table 31 597 IFIH1 yes AD Table 6277 IFIT1 no unknown Table 31 598 IFIT2 no unknown Table 31 599 IFIT3 nounknown Table 31 600 IFNAR1 no unknown Table 6 278 IFNAR2 yes AR Table 6279 IFNG no unknown Table 6 280 IFNGR1 yes AD AR Table 6 281 IFNGR2 yesAD AR Table 6 282 IFNLR1 no unknown Table 6 62 IGHM yes AR Table 31 601IGHMBP2 no unknown Table 31 602 IGKC yes AR Table 31 603 IGLL1 yes ARTable 6 283 IKBKB yes AD AR Table 6 284 IKBKG yes XLD XLR Table 6 285IKZF1 yes AD Table 6 286 IL10 yes AR Table 6 287 IL10RA yes AR Table 6288 IL10RB yes AR Table 6 289 IL12B yes AR Table 6 290 IL12RB1 yes ARTable 6 291 IL17F yes AD Table 6 292 IL17RA yes AR Table 6 293 IL17RCyes AR Table 31 604 IL1B no unknown Table 6 294 ILIRN yes AR Table 31605 IL21 yes AR Table 6 295 IL21R yes AD AR Table 6 296 IL2RA yes ARTable 6 297 IL2RG yes XLR Table 6 298 IL3 no unknown Table 31 606 IL36RNyes AR Table 31 607 IL4 no unknown Table 31 608 IL4R no unknown Table 6299 IL7 no unknown Table 6 300 IL7R yes AR Table 6 301 INO80 yes ARTable 31 609 INPP5D no unknown Table 31 610 IRAK1 yes XLR Table 31 611IRAK4 yes AD AR Table 6 302 IRF2BP2 yes AD Table 31 612 IRF3 yes ADTable 6 303 IRF7 yes AR Table 6 304 IRF8 yes AD AR Table 6 305 IRGM nounknown Table 6 306 ISG15 yes AR Table 6 307 ITCH yes AR Table 31 613ITGAM no unknown Table 31 614 ITGB2 yes AR Table 31 615 ITK yes AR Table25B 308 ITPKB no unknown Table 31 616 ITSN1 no unknown Table 31 617ITSN2 no unknown Table 6 309 JAGN1 yes AR Table 6 310 JAK1 yes AD ARTable 31 618 JAK3 yes AR Table 6 311 JMY no unknown Table 6 312 JUN nounknown Table 6 313 KANK1 no unknown Table 6 65 KAT6B no unknown Table 666 KCTD7 no unknown Table 6 67 KDM6A yes XLD XLR Table 31 619 KITLG nounknown Table 6 314 KMT2D yes AD Table 31 620 KRAS no AD Table 31 621LAMTOR2 yes AR Table 6 315 LARP4B no unknown Table 6 69 LAT yes AR Table31 622 LCK yes AR Table 25B 316 LCP2 no unknown Table 6 317 LIG1 yes ARTable 6 318 LIG4 yes AR Table 6 319 LPIN2 yes AR Table 31 623 LRBA yesAR Table 6 322 LRRK2 no unknown Table 31 624 LYST yes AR Table 6 323MAGEA9B no unknown Table 6 325 MAGT1 yes XLR Table 6; Table 25A 326 MALLno unknown Table 6 72 MALT1 yes AR Table 6 327 MAP3K14 yes AR Table 31625 MAP3K2 no unknown Table 6 328 MAPK1 no unknown Table 6 329 MAPK3 nounknown Table 6 330 MAPK9 no unknown Table 6 73 MASP2 yes AR Table 31626 MAVS no unknown Table 6 331 MB21D1 no unknown Table 31 627 MBL2 noAD Table 31 628 MCEE no unknown Table 6 74 MCM4 yes AR Table 31 629 MCM5no AR Table 31 630 MDC1 no unknown Table 31 631 MECP2 no XLD XLR Table 6332 MEF2C no AD Table 31 632 MEFV yes AD AR Table 31 633 MEX3C nounknown Table 6 333 MFN1 no unknown Table 31 634 MFN2 no unknown Table31 635 MGAT5 no unknown Table 6 75 MKL1 yes AR Table 6 89 MLH1 no AD ARTable 31 636 MMP9 no unknown Table 31 637 MOGS yes AR Table 31 638 MON1Ano unknown Table 31 639 MON1B no unknown Table 31 640 MRE11A no AR Table6 334 MS4A1 yes AR Table 6 335 MSH2 no AD AR Table 31 641 MSH5 no ARTable 31 642 MSH6 yes AR Table 31 643 MSN yes unknown Table 6 336 MTHFD1yes AR Table 6 337 MVK yes AD AR Table 31 644 MX1 no unknown Table 31645 MX2 no unknown Table 31 646 MYD88 yes AD AR Table 6 338 MYSM1 yes ARTable 31 647 NBAS yes AR Table 31 648 NBN yes AD AR Table 6 339 NCF1 yesAR Table 31 649 NCF2 yes AR Table 31 650 NCF4 yes AR Table 31 651 NCSTNyes AD Table 31 652 NFAT5 yes AD Table 31 653 NFIC no unknown Table 6340 NFIL3 no unknown Table 6 92 NFKB1 yes AD Table 6 341 NFKB2 yes ADTable 6 342 NFKBIA yes AD Table 6 343 NHEJ1 yes AR Table 6 344 NHP2 yesAR Table 31 654 NLRC4 yes AD Table 31 655 NLRP1 yes AR Table 31 656NLRP12 yes AD Table 6 93 NLRP2 no unknown Table 31 657 NLRP3 yes ADTable 6 345 NLRX1 no unknown Table 31 658 NOD1 no unknown Table 31 659NOD2 yes AD Table 6 346 NOP10 yes AR Table 31 660 NQO2 no unknown Table6 94 NRIP1 no unknown Table 6 95 NSMCE3 yes AR Table 31 661 OAS1 no ADTable 31 662 OAS2 no unknown Table 31 663 OAS3 no unknown Table 31 664OASL no unknown Table 31 665 ORAI1 yes AD AR Table 6 347 ORC4 no ARTable 31 666 OSTM1 yes AR Table 6 348 OTULIN yes AR Table 31 667 OVOL2no unknown Table 6 98 PARN yes AD AR Table 31 668 PCCA no AR Table 31669 PCCB no AR Table 31 670 PDCD1 no unknown Table 31 671 PDCD1LG2 nounknown Table 31 672 PDE3B no unknown Table 6 99 PDGFRA no unknown Table6 100 PDSS2 no unknown Table 6 101 PEPD yes AR Table 31 673 PGM3 yes ARTable 6 349 PHACTR4 no unknown Table 6 102 PIAS1 no unknown Table 6 103PIAS2 no unknown Table 6 350 PIK3CD yes AD Table 6 104 PIK3R1 yes AD ARTable 6 351 PINK1 no unknown Table 31 674 PKHD1 no unknown Table 6 105PLAU no unknown Table 31 675 PLAUR no unknown Table 31 676 PLCG1 nounknown Table 31 677 PLCG2 yes AD Table 6 352 PLD1 no AR Table 31 678PLEKHM1 yes AR Table 31 679 PLK1 no unknown Table 31 680 PLXNB1 nounknown Table 31 681 PMM2 no AR Table 31 682 PMS2 yes AR Table 6 353 PNPyes unknown Table 25B 354 PNPLA4 no unknown Table 6 107 PNPT1 no unknownTable 6 108 POLA1 yes XLR Table 6 355 POLE yes AR Table 6 356 POLE2 yesAR Table 31 683 PPM1A no unknown Table 31 684 PPP2R3B no unknown Table 6109 PRF1 yes AD AR Table 6 357 PRKCB no unknown Table 6 110 PRKCD yes ARTable 6 358 PRKCH no unknown Table 6 111 PRKDC yes AD AR Table 6 359PRKN no unknown Table 31 685 PROC no unknown Table 6 360 PRRC2A nounknown Table 31 686 PSEN1 yes AD Table 31 687 PSENEN yes AD Table 31688 PSMA7 no unknown Table 31 689 PSMB8 yes AR Table 6 361 PSTPIP1 yesAD Table 6 112 PTEN yes AD Table 6 362 PTPN2 no unknown Table 6 113PTPRC yes AR Table 6 363 PTPRN2 unknown Table 6 114 PURA no unknownTable 6 364 RAB27A yes AR Table 6 365 RAB37 no unknown Table 6 115 RABSAno unknown Table 31 690 RAB5B no unknown Table 31 691 RAB5C no unknownTable 31 692 RAB7A no unknown Table 6 366 RABGEF1 no unknown Table 6 367RAC2 yes AD Table 6 368 RAD50 no unknown Table 31 693 RAD51 no unknownTable 6 369 RAG1 yes AD AR Table25A; Table 25B 370 RAG2 yes AR Table 6371 RANBP2 yes AD Table 31 694 RASGRP1 yes AR Table 31 695 RBCK1 yes ARTable 6 372 RBFOX1 no unknown Table 6 116 RCC1 unknown Table 6 117 RELAno unknown Table 31 696 RELB yes AR Table 31 697 RFX5 yes AR Table 6 373RFXANK yes AR Table 6 374 RFXAP yes AR Table 6 375 RGCC no unknown Table6 118 RHOH yes AR Table 31 698 RHOQ no unknown Table 6 119 RIPK1 nounknown Table 6 376 RIPK3 no unknown Table 6 377 RLTPR yes AR Table 31699 RNASE3 no unknown Table 6 120 RNASEH2A yes AR Table 6 379 RNASEH2Byes AR Table 6 380 RNASEH2C yes AR Table 6 381 RNASEL no unknown Table 6382 RNF125 no unknown Table 31 700 RNF168 yes AR Table 6 383 RNF31 yesAR Table 6 384 RORC yes AR Table 31 701 RPSA yes AD Table 31 702 RPTORno unknown Table 6 123 RSAD2 no unknown Table 31 703 RTEL1 yes AR Table6 386 SALL2 no unknown Table 6 388 SAMD9 yes AD Table 31 704 SAMD9L yesAD Table 31 705 SAMHD1 yes AR Table 6 389 SBDS yes AR Table 6 390 SEMA3Eyes AD Table 31 706 SERPINA1 no AR Table 31 707 SERPINB2 no unknownTable 31 708 SERPINB4 no unknown Table 6 124 SERPINB6 no unknown Table 6125 SERPING1 yes AD Table 31 709 SH2D1A yes XLR Table 6 391 SH3BP2 yesAD Table 31 710 SHARPIN no unknown Table 6 392 SKIV2L no AR Table 6 393SLC17A5 no unknown Table 6 127 SLC29A3 yes AR Table 31 711 SLC35C1 yesAR Table 31 712 SLC37A4 yes AR Table 6 394 SLC3A2 no unknown Table 6 126SLC46A1 yes AR Table 6 395 SLC7A7 no AR Table 31 713 SLC8A1 no unknownTable 6 396 SLC9A1 no unknown Table 31 714 SMAD2 no unknown Table 6 397SMAD3 no unknown Table 6 398 SMAD4 no unknown Table 6 399 SMARCAL1 yesAR Table 31 715 SMARCD2 yes AR Table 31 716 SMC3 no AD Table 31 717SMURF2 no unknown Table 31 718 SNAP29 no unknown Table 6 400 SNCA nounknown Table 6 429 SNHG3 no unknown Table 6 128 SNX10 yes AR Table 6430 SNX5 no unknown Table 6 130 SOCS2 no unknown Table 6 131 SP110 yesAR Table 6 431 SP140 no unknown Table 6 432 SPINK5 yes AR Table 6 433SQSTM1 no unknown Table 6 434 SRP54 yes AD Table 31 719 ST8SIA5 nounknown Table 6 133 STAT1 yes AD AR Table25A; Table 25B 436 STAT2 yes ARTable 6 437 STAT3 yes AD Table 25B 438 STATSB yes AR Table 6 439 STIM1yes AD AR Table 6 440 STIM2 no unknown Table 6 134 STK3 no unknown Table25B; Table 26 135 STK4 yes AR Table 6 441 STN1 yes AR Table 31 720 STX11yes AR Table 6 442 STXBP2 yes AD AR Table 6 443 SYNCRIP no unknown Table6 444 TAP1 yes AR Table 6 446 TAP2 yes AR Table 6 447 TAPBP yes unknownTable 6 448 TAZ yes XLR Table 6 449 TBC1D15 no unknown Table 31 721TBC1D16 no unknown Table 6 136 TBC1D17 no unknown Table 31 722 TBK1 yesAD Table 6 450 TBX1 yes AD Table 6 451 TBXT no unknown Table 6 445 TCF3yes AD Table 31 723 TCIRG1 yes AD AR Table 6 452 TCN2 yes AR Table 31724 TEK no AD Table 31 725 TERT yes AD AR Table 31 727 TFPI no unknownTable 31 728 TFRC yes AR Table 31 729 THBD yes AD Table 31 730 THBS1 nounknown Table 31 731 TICAM1 yes AD AR Table 6 453 TINF2 yes AD Table 31732 TIRAP yes AR Table 31 733 TLR3 yes AD Table 6 454 TLR4 no unknownTable 6 455 TMC6 yes AR Table 31 734 TMC8 yes AR Table 31 735 TMEM173yes AD Table 6 456 TNF no unknown Table 6 457 TNFAIP3 yes AD Table 6 458TNFRSF10A no unknown Table 6 138 TNFRSF11A yes AD AR Table 6 459TNFRSF11B no AR Table 6 460 TNFRSF13B yes AD AR Table 6 461 TNFRSF13Cyes AR Table 6 139 TNFRSF17 no unknown Table 31 736 TNFRSF18 no unknownTable 6 140 TNFRSFIA yes AD Table 31 737 TNFRSF4 yes AR Table 6 462TNFRSF8 no unknown Table 6 463 TNFSF10 no unknown Table 31 738 TNFSF11yes AR Table 6 464 TNFSF12-TNFSF13 yes AD Table 6 465 TNFSF13B nounknown Table 31 740 TNIP1 no unknown Table 31 741 TP53 no AD AR Table 6466 TP53AIP1 no unknown Table 31 742 TPP1 yes AD AR Table 31 743 TPP2yes AR Table 31 744 TRAC yes AR Table 31 745 TRAF3 yes AD Table 6 467TRAF3IP2 yes AR Table 31 746 TRAF6 no unknown Table 6 468 TRAFD1 nounknown Table 6 141 TREX1 yes AD AR Table 6 469 TRIM25 no unknown Table31 747 TRIM37 no AR Table 31 748 TRNT1 yes AR Table 6 470 TRPM2 nounknown Table 6 142 TTC37 yes AR Table 31 749 TTC7A yes AR Table 6 471TYK2 yes AR Table 25B 144 UBD no unknown Table 31 750 UBE2N no unknownTable 6 145 UNC119 no AD Table 6 472 UNC13D yes AR Table 6 473 UNC93B1yes unknown Table 6 474 UNG yes AR Table 6 475 USB1 yes AR Table 31 751USP15 no unknown Table 31 752 USP18 yes AR Table 6 476 USP20 no unknownTable 6 477 USP21 no unknown Table 31 753 USP25 no unknown Table 31 754USP3 no unknown Table 31 755 VAPA no unknown Table 6 478 VAV1 no unknownTable 31 756 VCP no AD Table 6 479 VDAC1 no unknown Table 6 480 VDR noAD AR Table 31 757 VEGFA no unknown Table 31 758 VPS13B yes AR Table 6481 VPS45 yes AR Table 6 482 VSTM1 no unknown Table 6 147 VWA2 nounknown Table 6 148 WAS yes XLR Table25A; Table 25B 483 WASHC5 no AD ARTable 31 759 WDR1 yes AR Table 31 760 WEE1 no unknown Table 6 484 WIPF1yes AR Table 6; Table 25B 485 WRAP53 yes AR Table 31 761 XAF1 no unknownTable 31 762 XIAP yes XLD XLR Table 6 486 YBX1 no unknown Table 6 487YWHAZ no unknown Table 6 488 ZAP70 yes AD AR Table 6 489 ZBTB24 yes ARTable 6 490For the 663-genes list in Table 47, the following are provided: RefSeqGene Symbol, whether the gene is included in the IUIS-334 list (Picardet al. (2018) J Clin Immunol. 38(1):96-128; Bousfiha et al. (2018) JClin Immunol. 38(1):129-143), the Disease Model, Cross-referenced tablesthat also list a subset of the 663 genes, and Gene Number.

In some embodiments, stricter criteria can be used for the Disease Modeldesignation. For example, Table 6 uses AR, AD, XLR, and XLD diseasemodels based on the OMIM entries irrespective of whether the geneticdisease is a classical immunodeficiency disorder. Whereas, Table 47lists AR, AD, XLR, and XLD entries only for those genes that are on theIUIS-334 gene list. For example, the gene PKHD1 causes AR polycystickidney disease and is listed as an AR disease in Table 6 but with an“unknown” Disease Model in Table 47. However, those skilled in the artunderstand that additional disease phenotypes are often added to theclinical picture once more patients are identified. In Burgmaier et al.2019 (Sci Rep. 9(1):7919), patients are reported to have the immunephenotypes of thrombocytopenia, anemia, and leukopenia.

Example 28—DV Pipeline Variant Burden Summary Data

Top variants from the variant burden analyses were identified on thebasis of filtering criteria that were applied to both the Dis and RepPML cohorts (including a subset of functional annotation), followed bydetermining the subset of filtered variants that were found in bothcohorts. The filtering criteria used were:

-   -   A. 663-genes (het and hom files), IMPACT=HIGH or MODERATE, ≥2        EUR cases or ≥1 AFR case, FET ≤0.1, OR >1    -   B. All-genes (het and hom files) used 3 sets of filters:        -   1. IMPACT=HIGH, ≥3 EUR cases or ≥1 AFR case, FET ≤0.05, OR            >1        -   2. IMPACT=MODERATE, VARIANT CLASS=deletion or insertion, ≥3            EUR cases or ≥1 AFR case, FET ≤0.05, OR >1    -   3. IMPACT=MODERATE, VARIANT CLASS=SNV, PolyPhen=damaging and        SIFT=D (deleterious), ≥3 EUR cases or ≥2 AFR case, FET ≤0.05, OR        >1        After finding the set of overlapping variants for the Dis and        Rep cohorts according to the above filters, they were further        assessed for biology of the genes using PubMed and ranked as        follows: 1=strong biology, 2=medium biology, 3=unknown biology.        Variants were also excluded for: 1) very high PML case counts        (more likely to be false positives), 2) high frequency in one        ethnicity but not the other (greater likelihood that the variant        is benign as compared to a variant that is rare in both the EUR        and AFR ethnicities), and 3) presence in a chr X gene (such        variants are challenging to interpret as gender needs to be        taken into account). The top 27 variants from this set of        analyses and filtering criteria are listed in Tables 50A and        50B.

TABLE 50A Top 27 variants from DV pipeline variant burden analyses IUIConse- Poly Gene Variant (hg19) Source S-334 quence Impact Phen SIFT SEQID AIRE 21-45708278-G- 663 het yes missense moderate prob. tol. 3268, AAFR dam. 3523 ATM 11-108106443- 663 hom yes missense moderate benigntol. 3517 T-A AFR C8B 1-57409459-C- 663 het yes missense moderate poss.del. 3015, A AFR dam. 3502 CFHR2 1-196918605-A- 663 het yes missensemoderate benign tol. 3505 G AFR DNASE1L3 3-58191230-G- 663 het yesmissense moderate benign tol. 3508 T AFR DNER 2-230579019-G- 663 het nomissense moderate benign del. 3507 A NFE FCN2 9-137779251-G- all het nomissense moderate prob. del. 3515 A NFE dam. FCN3 1-27699670- 663 hetyes frameshift high n/a; n/a; 3500 AG-A NFE LOF LOF GFI1 1-92946625-G-663 het yes missense moderate benign tol. 3503 C AFR HIVEP31-42047208-C- 663 het no missense moderate benign tol. 3501 G AFR IFIH12-163136505-C- U.S. Pat. No. yes Splice high n/a; n/a; 1041, G10,240,205; donor LOF LOF 3506 663 het NFE; all het NFE IGLL122-23915583-T- 663 het yes missense moderate benign tol. 3524 C NFEIGLL1 22-23915745-G- U.S. Pat. No. yes missense moderate benign del.1325, A 10,240,205 3525 LIG1 19-48643270-C- 663 het yes missensemoderate poss. del. 3522 T AFR dam. LRBA 4-151793903-T- 663 het yesmissense moderate benign tol. 3509 C NFE LY9 1-160769595- all het noframeshift high n/a; n/a; 3504 AG-A AFR LOF LOF MCM5 22-35806756-G- 663het no missense moderate poss. tol. 3273, A NFE dam. 3526 MDC16-30673359-T- 663 het no missense moderate benign tol. 3511 G NFE NQO26-3015818-G-A 663 het no missense moderate prob. del. 3510 AFR dam.PKHD1 6-51798908-C-T 663 het no missense moderate prob. del. 3514 AFRdam. PLCG2 16-81942175-A- U.S. Pat. No. yes missense moderate benigndel. 1263, G 10,240,205 3519 PRAM1 19-8564523-T- all het no missensemoderate poss. del. 3521 G NFE; all dam. het AFR SERPINA1 14-94847262-T-663 het no missense moderate prob. del. 3214, A NFE dam. 3518 STXBP219-7712287-G- U.S. Pat. No. yes missense moderate prob. del. 1291, C10,240,205; dam. 3520 663 het NFE TAP1 6-32814942-C-T 663 het yesmissense moderate prob. del. 3512 NFE; dam 663 hom AFR TAP16-32816772-C- 663 het yes missense moderate benign tol. 3513 A NFE; 663hom AFR TCIRG1 11-67818269-G- U.S. Pat. No. yes missense mod benign tol.1185, A 10,240,205 3516Table 50A lists the Gene, Variant position (hg19), Source of the variant(663-genes or all-genes het or hon variant burden files, and/or fromU.S. Pat. No. 10,240,205), functional prediction (Consequence, Impact,PolyPhen, SIFT), and SEQ IDs. Loss of Function variants (LOF) areindicated in the Polyphen and SIFT columns as n/a/LOF (e.g., no aminoacid prediction information was available from these algorithms but thegnomAD annotation indicates “LOF: High-confidence”).

TABLE 50B Top 27 variants from DV pipeline variant burden analyses,distribution of PML cases by cohort (Dis and Rep) and ethnicity (EUR andAFR) Dis EUR Rep EUR Dis AFR Rep AFR (n = 49) (n = 87) (n = 21) (n = 28)Gene Variant (hg19) Het Hom Het Hom Het Hom Het Hom AIRE 21-45708278-G-A0 0 0 0 1 0 1 0 ATM 11-108106443-T-A 2 0 0 0 7 3 8 3 C8B 1-57409459-C-A3 0 0 0 1 0 1 0 CFHR2 1-196918605-A-G 0 0 0 0 1 0 2 0 DNASE1L33-58191230-G-T 0 0 0 0 1 0 1 0 DNER 2-230579019-G-A 4 0 4 0 0 0 0 0 FCN29-137779251-G-A 3 0 3 0 0 0 1 0 FCN3 1-27699670-AG-A 5 0 7 0 0 0 2 0GFI1 1-92946625-G-C 2 0 0 0 1 0 1 0 HIVEP3 1-42047208-C-G 8 0 8 0 2 0 30 IFIH1 2-163136505-C-G 6 0 5 0 1 0 0 0 IGLL1 22-23915583-T-C 2 0 3 0 00 0 0 IGLL1 22-23915745-G-A 2 0 1 0 1 0 0 0 LIG1 19-48643270-C-T 1 0 0 01 0 1 0 LRBA 4-151793903-T-C 6 0 9 0 0 0 1 0 LY9 1-160769595-AG-A 0 0 00 1 0 1 0 MCM5 22-35806756-G-A 3 0 4 0 0 0 0 0 MDC1 6-30673359-T-G 2 0 50 0 0 0 0 NQO2 6-3015818-G-A 0 0 0 0 1 0 2 0 PKHD1 6-51798908-C-T 0 0 00 2 0 1 0 PLCG2 16-81942175-A-G 3 0 3 0 4 0 1 0 PRAM1 19-8564523-T-G 271 14 4 6 0 4 1 SERPINA1 14-94847262-T-A 7 0 12 0 0 0 1 0 STXBP219-7712287-G-C 2 0 2 0 0 0 0 0 TAP1 6-32814942-C-T 6 0 9 1 6 2 5 2 TAP16-32816772-C-A 6 0 9 1 6 2 5 2 TCIRG1 11-67818269-G-A 0 0 0 0 4 0 3 0Table 50B shows the same top 27 variants listed in Table 50A, but withthe distribution of number of PML cases that had a het or hom genotypeand a breakdown by cohort (Dis or Rep) and ethnicity (EUR or AFR).

Example 29—DV Pipeline Variant Burden Statistical Analyses

The set of 27 variants from the DV pipeline variant burden analyses (seeTables 50A and 50B) were ranked based on FET and OR values for fourtypes of analyses: EUR only, AFR only, EUR+AFR normalized (norm.)wherein the gnomAD cohort sizes were adjusted to match the relativeproportion of EUR (NFE in gnomAD) and AFR PML cases in the total cohort(n=185), and EUR+AFR summed (sum.) wherein the subject data for thegnomAD NFE and AFR cohorts were simply added together. Three sets ofstatistical analyses were performed using three publically availableresources (gnomAD exome, gnomAD genome, and TGP exome), but only thegnomAD exome analyses are presented in Tables 51-62 as the results werecomparable for nearly all variants. For each set of 3 tables (tier 1,tier 2, and tiers 1 and 2 combined), FET and OR were calculated for all27 variants, variants were sorted on OR (descending), and variants withFET >0.05 were excluded. For Tier 1 variants (Tables 51, 54, 57, and60), preference was given to variants with OR >3 and only moderatefrequency in PML cases (e.g., PRAM119-8564523-T-G was considered toofrequent). The “Reads” listed in the tables corresponds to the readcounts in the sequencing data (e.g., the number of individuals sampledfor the variant). Tables 51 and 54 also have a Panel rank wherein thetop 7 EUR variants and top 10 AFR variants are assigned a rank that isused in Tables 63A-64B.

TABLE 51 7 EUR variants (tier 1) with FET and OR values PML All EURgnomAD NFE Dominant Model Panel Gene Variant (hg19) Het Hom Reads HetHom Reads FET OR rank IGLL1 22-23915745-G- 3 0 136 42 0 56703 1.77E−0430.42 1 A MDC1 6-30673359-T- 7 0 136 302 0 54608 1.34E−05 9.76 2 GSTXBP2 19-7712287-G- 4 0 136 267 0 55798 4.46E−03 6.30 3 C FCN29-137779251-G- 6 0 136 461 1 56457 9.85E−04 5.59 4 A IGLL122-23915583-T- 5 0 136 446 0 56811 4.70E−03 4.82 5 C MCM5 22-35806756-G-7 0 136 665 7 56875 1.28E−03 4.54 6 A IFIH1 2-163136505-C- 11 0 136 12256 56438 2.19E−04 3.95 7 G

TABLE 52 9 EUR variants (tier 2) with FET and OR values PML All EURgnomAD NFE Dominant Model Gene Variant (hg19) Het Hom Reads Het HomReads FET OR PRAM1 19-8564523-T-G 41 5 136 2076 250 30728 1.65E−18 6.24ATM 11-108106443-T-A 2 0 136 143 0 56802 4.74E−02 5.91 TAP16-32816772-C-A 15 1 135 2250 26 55054 1.61E−04 3.12 TAP1 6-32814942-C-T15 1 136 2258 28 55157 1.80E−04 3.08 PLCG2 16-81942175-A-G 6 0 136 831 256290 1.64E−02 3.07 FCN3 1-27699670-AG-A 12 0 136 1826 24 56778 1.77E−032.87 DNER 2-230579019-G-A 8 0 136 55 3 2670 1.32E−02 2.81 SERPINA114-94847262-T-A 19 0 136 3946 105 56878 4.25E−03 2.12 LRBA4-151793903-T-C 15 0 136 3046 62 55340 1.32E−02 2.08

TABLE 53 16 EUR variants (tiers 1 and 2) with FET and OR values PML AllEUR gnomAD NFE Dominant Model Gene Variant (hg19) Het Hom Reads Het HomReads FET OR IGLL1 22-23915745-G-A 3 0 136 42 0 56703 1.77E−04 30.42MDC1 6-30673359-T-G 7 0 136 302 0 54608 1.34E−05 9.76 STXBP219-7712287-G-C 4 0 136 267 0 55798 4.46E−03 6.30 PRAM1 19-8564523-T-G 415 136 2076 250 30728 1.65E−18 6.24 ATM 11-108106443-T-A 2 0 136 143 056802 4.74E−02 5.91 FCN2 9-137779251-G-A 6 0 136 461 1 56457 9.85E−045.59 IGLL1 22-23915583-T-C 5 0 136 446 0 56811 4.70E−03 4.82 MCM522-35806756-G-A 7 0 136 665 7 56875 1.28E−03 4.54 IFIH1 2-163136505-C-G11 0 136 1225 6 56438 2.19E−04 3.95 TAP1 6-32816772-C-A 15 1 135 2250 2655054 1.61E−04 3.12 TAP1 6-32814942-C-T 15 1 136 2258 28 55157 1.80E−043.08 PLCG2 16-81942175-A-G 6 0 136 831 2 56290 1.64E−02 3.07 FCN31-27699670-AG-A 12 0 136 1826 24 56778 1.77E−03 2.87 DNER2-230579019-G-A 8 0 136 55 3 2670 1.32E−02 2.81 SERPINA1 14-94847262-T-A19 0 136 3946 105 56878 4.25E−03 2.12 LRBA 4-151793903-T-C 15 0 136 304662 55340 1.32E−02 2.08

TABLE 54 10 AFR variants (tier 1) with FET and OR values PML All AFRgnomAD AFR Dominant Model Panel Gene Variant (hg19) Het Hom Reads HetHom Reads FET OR rank LY9 1-160769595-AG-A 2 0 49 0 0 8123 3.52E−05855.11 1 LIG1 19-48643270-C-T 2 0 49 1 0 8126 1.05E−04 339.72 2 PKHD16-51798908-C-T 3 0 49 15 0 8127 1.55E−04 35.15 3 AIRE 21-45708278-G-A 20 49 17 0 8079 5.70E−03 20.14 4 GFI1 1-92946625-G-C 2 0 49 19 0 77567.51E−03 17.29 5 CFHR2 1-196918605-A-G 3 0 49 37 0 8027 1.77E−03 14.07 6NQO2 6-3015818-G-A 3 0 49 39 0 8128 1.97E−03 13.51 7 C8B 1-57409459-C-A2 0 49 28 0 8128 1.38E−02 12.29 8 DNASE1L3 3-58191230-G-T 2 0 49 32 08126 1.75E−02 10.75 9 PLCG2 16-81942175-A-G 5 0 49 128 0 7719 1.42E−036.73 10

TABLE 55 3 AFR variants (tier 2) with FET and OR values PML All AFRgnomAD AFR Dominant Model Gene Variant (hg19) Het Hom Reads Het HomReads FET OR PRAM1 19-8564523-T-G 10  1 49 136 4 6351 1.18E−08 12.82 HIVEP3 1-42047208-C-G 5 0 49 175 2 8041 4.67E−03 5.05 TCIRG111-67818269-G-A 7 0 49 318 1 8113 3.08E−03 4.07

TABLE 56 13 AFR variants (tiers 1 and 2) with FET and OR values PML AllAFR gnomAD AFR Dominant Model Gene Variant (hg19) Het Hom Reads Het HomReads FET OR LY9 1-160769595-AG-A 2 0 49 0 0 8123 3.52E−05 855.11 LIG119-48643270-C-T 2 0 49 1 0 8126 1.05E−04 339.72 PKHD1 6-51798908-C-T 3 049 15 0 8127 1.55E−04 35.15 AIRE 21-45708278-G-A 2 0 49 17 0 80795.70E−03 20.14 GFI1 1-92946625-G-C 2 0 49 19 0 7756 7.51E−03 17.29 CFHR21-196918605-A-G 3 0 49 37 0 8027 1.77E−03 14.07 NQO2 6-3015818-G-A 3 049 39 0 8128 1.97E−03 13.51 PRAM1 19-8564523-T-G 10  1 49 136 4 63511.18E−08 12.82 C8B 1-57409459-C-A 2 0 49 28 0 8128 1.38E−02 12.29DNASE1L3 3-58191230-G-T 2 0 49 32 0 8126 1.75E−02 10.75 PLCG216-81942175-A-G 5 0 49 128 0 7719 1.42E−03 6.73 HIVEP3 1-42047208-C-G 50 49 175 2 8041 4.67E−03 5.05 TCIRG1 11-67818269-G-A 7 0 49 318 1 81133.08E−03 4.07

TABLE 57 13 EUR + AFR variants (tier 1) with FET and OR values(normalized) PML All gnomAD NFE + AFR Dominant EUR + AFR (norm.) ModelGene Variant (hg19) Het Hom Reads Het Hom Reads FET OR PKHD16-51798908-C-T 3 0 185 6 0 43916 5.99E−06 120.00 LY9 1-160769595-AG-A 20 185 6 0 43924 4.82E−04 79.75 CFHR2 1-196918605-A-G 3 0 185 10 0 437522.04E−05 72.02 NQO2 6-3015818-G-A 3 0 185 12 0 43941 3.18E−05 60.30 AIRE21-45708278-G-A 2 0 185 8 0 43685 7.78E−04 59.62 IGLL1 22-23915745-G-A 40 185 58 0 43836 1.39E−04 16.67 TCIRG1 11-67818269-G-A 7 0 185 227 043910 6.39E−05 7.57 ATM 11-108106443-T-A 17 6 185 797 88 43909 6.97E−126.90 MDC1 6-30673359-T-G 7 0 185 251 0 42164 1.50E−04 6.57 PRAM119-8564523-T-G 51 6 185 1562 185 24271 2.94E−21 5.74 FCN29-137779251-G-A 7 0 185 342 1 43653 7.60E−04 4.96 STXBP2 19-7712287-G-C4 0 185 198 0 43049 1.13E−02 4.78 PLCG2 16-81942175-A-G 11 0 185 645 143425 1.27E−04 4.19

TABLE 58 8 EUR + AFR variants (tier 2) with FET and OR values(normalized) PML All gnomAD NFE + AFR Dominant EUR + AFR (norm.) ModelGene Variant (hg19) Het Hom Reads Het Hom Reads FET OR TAP16-32816772-C-A 26 5 184 2144 52 42515 7.80E−09 3.72 TAP1 6-32814942-C-T26 5 185 2140 53 42544 8.50E−09 3.70 GFI1 1-92946625-G-C 4 0 185 256  140597 3.16E−02 3.47 IGLL1 22-23915583-T-C 5 0 185 352  0 43910 1.78E−023.44 MCM5 22-35806756-G-A 7 0 185 494  5 43964 5.71E−03 3.43 IFIH12-163136505-C-G 12 0 185 910  4 43635 6.16E−04 3.24 FCN3 1-27699670-AG-A14 0 185 1448 18 43889 5.84E−03 2.37 SERPINA1 14-94847262-T-A 20 0 1852934 77 43966 4.05E−02 1.65

TABLE 59 21 EUR + AFR variants (tiers 1 and 2) with FET and OR values(normalized) PML All gnomAD NFE + AFR Dominant EUR + AFR (norm.) ModelGene Variant (hg19) Het Hom Reads Het Hom Reads FET OR PKHD16-51798908-C-T 3 0 185 6 0 43916 5.99E−06 120.00 LY9 1-160769595-AG-A 20 185 6 0 43924 4.82E−04 79.75 CFHR2 1-196918605-A-G 3 0 185 10 0 437522.04E−05 72.02 NQO2 6-3015818-G-A 3 0 185 12 0 43941 3.18E−05 60.30 AIRE21-45708278-G-A 2 0 185 8 0 43685 7.78E−04 59.62 IGLL1 22-23915745-G-A 40 185 58 0 43836 1.39E−04 16.67 TCIRG1 11-67818269-G-A 7 0 185 227 043910 6.39E−05 7.57 ATM 11-108106443-T-A 17 6 185 797 88 43909 6.97E−126.90 MDC1 6-30673359-T-G 7 0 185 251 0 42164 1.50E−04 6.57 PRAM119-8564523-T-G 51 6 185 1562 185 24271 2.94E−21 5.74 FCN29-137779251-G-A 7 0 185 342 1 43653 7.60E−04 4.96 STXBP2 19-7712287-G-C4 0 185 198 0 43049 1.13E−02 4.78 PLCG2 16-81942175-A-G 11 0 185 645 143425 1.27E−04 4.19 TAP1 6-32816772-C-A 26 5 184 2144 52 42515 7.80E−093.72 TAP1 6-32814942-C-T 26 5 185 2140 53 42544 8.50E−09 3.70 GFI11-92946625-G-C 4 0 185 256 1 40597 3.16E−02 3.47 IGLL1 22-23915583-T-C 50 185 352 0 43910 1.78E−02 3.44 MCM5 22-35806756-G-A 7 0 185 494 5 439645.71E−03 3.43 IFIH1 2-163136505-C-G 12 0 185 910 4 43635 6.16E−04 3.24FCN3 1-27699670-AG-A 14 0 185 1448 18 43889 5.84E−03 2.37 SERPINA114-94847262-T-A 20 0 185 2934 77 43966 4.05E−02 1.65

TABLE 60 12 EUR + AFR variants (tier 1) with FET and OR values (summed)PML All gnomAD NFE + AFR EUR + AFR (sum.) Dominant Model Gene Variant(hg19) Het Hom Reads Het Hom Reads FET OR LY9 1-160769595-AG-A 2 0 185 80 64946 3.56E−04 88.57 PKHD1 6-51798908-C-T 3 0 185 18 0 64937 2.89E−0559.42 AIRE 21-45708278-G-A 2 0 185 22 0 64592 2.15E−03 32.06 CFHR21-196918605-A-G 3 0 185 37 0 64650 2.09E−04 28.78 NQO2 6-3015818-G-A 3 0185 41 0 64972 2.74E−04 26.11 IGLL1 22-23915745-G-A 4 0 185 146 0 648269.30E−04 9.79 PRAM1 19-8564523-T-G 51  6 185 2212 254 37079 5.81E−236.25 MDC1 6-30673359-T-G 7 0 185 411 0 62235 2.71E−04 5.91 FCN29-137779251-G-A 7 0 185 471 1 64574 4.92E−04 5.34 STXBP2 19-7712287-G-C4 0 185 274 0 63462 9.08E−03 5.10 TCIRG1 11-67818269-G-A 7 0 185 512 164920 7.71E−04 4.94 PLCG2 16-81942175-A-G 11  0 185 959 2 64009 1.34E−044.15

TABLE 61 11 EUR + AFR variants (tier 2) with FET and OR values (summed)gnomAD NFE + AFR Dominant PML All EUR + AFR (sum.) Model Gene Variant(hg19) Het Hom Reads Het Hom Reads FET OR LIG1 19-48643270-C-T 3 0 185281 0 64971 4.77E−02 3.79 MCM5 22-35806756-G-A 7 0 185 683 7 650033.97E−03 3.67 GFI1 1-92946625-G-C 4 0 185 361 1 60185 2.67E−02 3.65IFIH1 2-163136505-C-G 12 0 185 1262 6 64538 3.48E−04 3.46 IGLL122-23915583-T-C 5 0 185 537 0 64915 1.98E−02 3.33 ATM 11-108106443-T-A17 6 185 2755 333 64928 2.83E−05 2.84 TAP1 6-32814942-C-T 26 5 185 4070149 62693 2.63E−06 2.79 TAPI 6-32816772-C-A 26 5 184 4101 149 627672.65E−06 2.79 FCN3 1-27699670-AG-A 14 0 185 2224 26 64892 6.97E−03 2.28LRBA 4-151793903-T-C 16 0 185 3116 62 63322 4.01E−02 1.79 SERPINA114-94847262-T-A 20 0 185 4073 106 65006 2.30E−02 1.76

TABLE 62 23 EUR + AFR variants (tiers 1 and 2) with FET and OR values(summed) Variant PML AIL EUR + AFR gnomAD NFE + AFR (sum.) DominantModel Gene (hg19) Het Hom Reads Het Hom Reads FET OR LY91-160769595-AG-A 2 0 185 8 0 64946 3.56E−04 88.57 PKHD1 6-51798908-C-T 30 185 18 0 64937 2.89E−05 59.42 AIRE 21-45708278-G-A 2 0 185 22 0 645922.15E−03 32.06 CFHR2 1-196918605-A-G 3 0 185 37 0 64650 2.09E−04 28.78NQO2 6-3015818-G-A 3 0 185 41 0 64972 2.74E−04 26.11 IGLL122-23915745-G-A 4 0 185 146 0 64826 9.30E−04 9.79 PRAM1 19-8564523-T-G51 6 185 2212 254 37079 5.81E−23 6.25 MDC1 6-30673359-T-G 7 0 185 411 062235 2.71E−04 5.91 FCN2 9-137779251-G-A 7 0 185 471 1 64574 4.92E−045.34 STXBP2 19-7712287-G-C 4 0 185 274 0 63462 9.08E−03 5.10 TCIRG111-67818269-G-A 7 0 185 512 1 64920 7.71E−04 4.94 PLCG2 16-81942175-A-G11 0 185 959 2 64009 1.34E−04 4.15 LIG1 19-48643270-C-T 3 0 185 281 064971 4.77E−02 3.79 MCM5 22-35806756-G-A 7 0 185 683 7 65003 3.97E−033.67 GFI1 1-92946625-G-C 4 0 185 361 1 60185 2.67E−02 3.65 IFIH12-163136505-C-G 12 0 185 1262 6 64538 3.48E−04 3.46 IGLL122-23915583-T-C 5 0 185 537 0 64915 1.98E−02 3.33 ATM 11-108106443-T-A17 6 185 2755 333 64928 2.83E−05 2.84 TAP1 6-32814942-C-T 26 5 185 4070149 62693 2.63E−06 2.79 TAP1 6-32816772-C-A 26 5 184 4101 149 627672.65E−06 2.79 FCN3 1-27699670-AG-A 14 0 185 2224 26 64892 6.97E−03 2.28LRBA 4-151793903-T-C 16 0 185 3116 62 63322 4.01E−02 1.79 SERPINA114-94847262-T-A 20 0 185 4073 106 65006 2.30E−02 1.76

Example 30—Variant Panels with Diagnostic Yield and Population ImpactAssessment

Variant panels consisting of the top 7 EUR variants (Table 51) and top10 AFR variants (Table 54) were assessed for their non-redundantdiagnostic yield in the PML cases (e.g., a PML case with ≥2 panelvariants was counted only once). These panels were similarly assessed inTGP exome data from 440 AFR and 436 EUR subjects, whoseGRCh37-referenced BAM files were downloaded and re-analyzed using the DVpipeline. Tables 63A and 64A show the results for EUR and AFR PML casesvs. TGP controls, respectively, wherein the PML Panel Frequencycorresponds to the diagnostic yield and the Frequency Ratio reflects thelevel of enrichment of the panel variants in the PML cases. The FET andOR values correspond to the number of PML cases and TGP controls thathave any one or more of 3 variants, 4 variants, etc. for a given panel.

Tables 63B and 64B contain the population impact assessment results asdescribed in Tonk et al. (2016) Pharmacogenomics J. 17(4):386-392, forthe following: Sensitivity, Specificity, Positive predictive value(PPV), Negative predictive value (NPV), Population attributablefrequency (PAF), Number needed to treat (NNT), and Number needed togenotype (NNG).

TABLE 63A EUR 7-variant panel, diagnostic yield and FET and OR valuesEUR PML EUR TGP Frequency Variants Cases PML Panel Subjects TGP PanelRatio Tested (n = 136) Frequency (n = 436) Frequency (PML/TGP) FET OREUR Top 3 14 0.103 5 0.011 8.98 4.02E−06 9.89 EUR Top 4 19 0.140 7 0.0168.70 6.90E−08 9.95 EUR Top 5 24 0.176 11 0.025 6.99 7.45E−09 8.28 EURTop 6 31 0.228 16 0.037 6.21 1.32E−10 7.75 EUR Top 7 40 0.294 30 0.0694.27 1.06E−10 5.64

TABLE 63B EUR 7-variant panel, population impact assessment RelativeRisk Variants Risk Difference Tested Sensitivity Specificity PPV NPV(RR) (RD) PAF NNT NNG EUR Top 3  9.1% 99.0% 10.7% 98.8% 8.94 0.09 0.0811 953 EUR Top 4 15.1% 98.2% 10.2% 98.9% 9.04 0.09 0.13 11 574 EUR Top 517.6% 97.5% 8.4% 98.9% 7.66 0.07 0.15 14 503 EUR Top 6 22.7% 96.4% 7.6%99.0% 7.24 0.07 0.20 15 394 EUR Top 7 25.8% 94.2% 5.5% 99.0% 5.38 0.040.21 22 366

TABLE 64A AFR 10-variant panel, diagnostic yield and FET and OR valuesAFR PML AFR TGP Frequency Variants Cases PML Panel Subjects TGP PanelRatio Tested (n = 49) Frequency (n = 440) Frequency (PML/TGP) FET OR AFRTop 6 14 0.286 5 0.011 25.14 1.29E−11 34.80 AFR Top 7 17 0.347 6 0.01425.44 3.97E−14 38.43 AFR Top 8 19 0.388 6 0.014 28.44 3.18E−16 45.81 AFRTop 9 20 0.408 6 0.014 29.93 2.66E−17 49.89  AFR Top 10 23 0.469 10 0.023 20.65 1.90E−18 38.04

TABLE 64B AFR 10-variant panel, population impact assessment RelativeRisk Variants Risk Difference Tested Sensitivity Specificity PPV NPV(RR) (RD) PAF NNT NNG AFR Top 6 22.6% 99.2% 26.4% 99.0% 25.89 0.25 0.224 355 AFR Top 7 31.7% 98.8% 25.9% 99.1% 28.73 0.25 0.31 4 251 AFR Top 840.0% 98.6% 26.9% 99.2% 33.78 0.26 0.39 4 198 AFR Top 9 47.0% 98.3%26.2% 99.3% 37.09 0.25 0.46 4 168  AFR Top 10 56.5% 96.7% 18.4% 99.4%31.22 0.18 0.55 6 141

Example 31—Variant Panels with Summary Information

Table 65 shows the breakdown of PML cases with a variant from the set of17 variants (7 FUR and 10 AFR, Tables 51 and 54). In general, they aredistributed across genders, ethnicities, and primary diseases. Forexample, all 7 EUR variants are found in two or more Primary Diseases(MS, HIV, Blood Cancers, Other). In contrast, about half of the 10 AFRvariants are found only in HIV PML patients, but this is not surprisinggiven the large proportion of AFR HIV PML cases (48 of 49) in the PMLcohort (see Table 46).

Table 66 lists the dbSNP ID numbers for the set of 17 variants (7 EURand 10 AFR, Tables 51 and 54), along with PubMed PMID numbers forsupporting biology in the literature (see also Tables 6 and 31 foradditional PMID citations for a subset of the genes).

TABLE 65 EUR 7-variant and AFR 10-variant panels, distribution of PMLcases by cohort, gender, ethnicity, and primary disease Panel Dis RepPML Males Females AFR EUR MS HIV Blood Other Source Cohort Cohort TOTAL(n = (n = (n = (n = (n = (n = Cancers (n = Gene Variant (hg19) Rank (n =70) (n = 115) (n = 185) 118) 67) 49) 136) 15) 125) (n = 22) 23) IGLL122-23915745-G-A EUR 1 3 1 4 2 2 1 3 1 3 0 0 MDC1 6-30673359-T-G EUR 2 27 9 9 0 1 8 0 8 0 1 STXBP2 19-7712287-G-C EUR 3 2 2 4 1 3 0 4 2 1 0 1FCN2 9-137779251-G-A EUR 4 3 4 7 4 3 1 6 2 4 1 0 IGLL1 22-23915583-T-CEUR 5 2 3 5 1 4 0 5 0 1 4 0 MCM5 22-35806756-G-A EUR 6 3 4 7 4 3 0 7 1 50 1 IFIH1 2-163136505-C-G EUR7 7 5 12  9 3 1 11  1 8 1 2 LY91-160769595-AG-A AFR 1 1 1 2 1 1 2 0 0 1 0 1 LIG1 19-48643270-C-T AFR 22 1 3 3 0 2 1 0 3 0 0 PKHD1 6-51798908-C-T AFR 3 2 1 3 1 2 3 0 0 3 0 0AIRE 21-45708278-G-A AFR 4 1 1 2 0 2 2 0 0 2 0 0 GFI1 1-92946625-G-C AFR5 3 1 4 2 2 2 2 0 3 1 0 CFHR2 1-196918605-A-G AFR 6 1 2 3 2 1 3 0 0 3 00 NQO2 6-3015818-G-A AFR 7 1 2 3 2 1 3 0 0 3 0 0 C8B 1-57409459-C-A AFR8 4 1 5 2 3 2 3 1 3 1 0 DNASE1L3 3-58191230-G-T AFR 9 1 1 2 2 0 2 0 0 20 0 PLCG2 16-81942175-A-G  AFR 10 7 4 11  9 2 5 6 1 8 0 2

TABLE 66 EUR 7-variant and AFR 10-variant panels, dbSNP IDs andsupporting biology Panel Source Supporting Gene Variant (hg19) dbSNP IDRank Biology-PubMed (PMID) IGLL1 22-23915745-G-A rs143780139 EUR 131291582 MDC1 6-30673359-T-G rs143258964 EUR 2 30453211, 30541848 STXBP219-7712287-G-C rs35490401 EUR 3 28983403, 29599780 FCN2 9-137779251-G-Ars76267164 EUR 4 20375618, 25251245, 28894916, 30747617, 30868077 IGLL122-23915583-T-C rs1064421 EUR 5 31291582 MCM5 22-35806756-G-A rs2230933EUR 6 27414250 IFIH1 2-163136505-C-G rs35337543 EUR 7 22648297,28716935, 28475461, 28553952, 30201512 LY9 1-160769595-AG-A rs763811636AFR 1 15905546, 26667173, 27054584, 27482100, 30791129 LIG119-48643270-C-T rs3730947 AFR 2 30395541 PKHD1 6-51798908-C-Trs199589074 AFR 3 31138820 AIRE 21-45708278-G-A rs148012328 AFR 431167928 GFI1 1-92946625-G-C rs149914857 AFR 5 26447191, 31004086 CFHR21-196918605-A-G rs148175483 AFR 6 29686068 NQO2 6-3015818-G-Ars148024596 AFR 7 27692612 C8B 1-57409459-C-A rs139498867 AFR 8 31270218DNASE1L3 3-58191230-G-T rs12491947 AFR 9 28533778, 30593563, 30026744PLCG2 16-81942175-A-G rs75472618 AFR 10 28714976

Example 32—Updated Drug Information

Immunosuppressive medications are a broad and expanding class oftherapeutics, which includes generic versions of biologics (termedbiosimilars). Drugs, such as those on the market that may be linked toPML risk, either now or in the future, include but are not limited to:diroximel fumarate (e.g. VUMERITY), siponimod (e.g. MAYZENT), golimumab(e.g. SIMPONI), elotuzumab (e.g. EMPLICITI), idebenone, ravulizimab-cwvz(e.g. (ULTOMIRIS), letrozole (e.g. FEMARA), voriconazole (e.g. VFEND),dalfampridine (e.g. AMPYRA), ambrisentan (e.g. LETAIRIS), pegfilgrastim(e.g. NEULASTA), simvastatin, adrenocorticotropic hormone, lipoic acid,and oxcarbazepine.

Immunosuppressive medications undergoing clinical trials that may linkedto PML risk before or after drug approval include but are not limitedto: elezanumab, nerispirdine, daprolizumab pegol, etrolizumab,abrilumab, evobrutinib, amiselimod, ceralifimod, clemastine, sunphenonepigallocatechin-gallate, and andrographolides (a botanical medicinalherb also known as IB-MS).

In addition, other molecules of interest include but are not limited toBNZ-1, IMU-838, SAR442168/PRN2246, B11B033, BIIB059, BIIB061, AJM300,EK-12 (a neuropeptide combination of metenkefalin and tridecactide), andCHS-131.

Some drugs of interest as immunosuppressive medications have alternatenames reported in FDA databases, such as fingolimod vs. fingolimodhydrochloride, mycophenolate mofetil vs. mycophenolate mofetilhydrochloride, tacrolimus vs. tacrolimus anhydrous, bendamustine vs.bendamustine hydrochloride, doxorubicin vs. doxorubicin hydrochloride,and certolizumab vs. certolizumab pegol.

Some HIV treatments have also been linked to cases of PML in the FDAdatabase, such as ritonavir (e.g. NORVIR), enfuvirtida (e.g. FUZEON),and maraviroc (e.g. SELZENTRY).

Approved medications and/or molecules of interest that have the samemechanism of action as natalizumab, and therefore may linked to PML,include but are not limited to levocabastine, TR-14035, and R-411.

TABLE 67 Examples of biosimilars Orignal Brand Biosimilar Name GenericName Biosimilar Name Brand/Code Name Rituxan rituximab rituximab-abbsTruxima Rituxan rituximab rituximab-pvvr Ruxience Rituxan rituximabRimimyo Rituxan rituximab Rixathon Rituxan rituximab ABP 798 Rituxanrituximab RTXM83 Remicade infliximab infliximab-dyyb Inflectra Remicadeinfliximab infliximab-abda Renflexis Remicade infliximab infliximab-qbtxIxifi/Zessly Remicade infliximab ABP 710 Remicade infliximab RemsimaHumira adalimumab adalimumab-atto Amjevita Humira adalimumabadalimumab-adaz Hyrimoz Humira adalimumab adalimumab-bwwd HadalmiaHumira adalimumab adalimumab-adbm Cyltezo Humira adalimumab Hulio Humiraadalimumab Imraldi Humira adalimumab PF-06410293 Humira adalimumabCT-P17 Humira adalimumab CHS-1420 Humira adalimumab M923/BAX923 Humiraadalimumab MYL-1401A Humira adalimumab LBAL Humira adalimumab MSB11022(Idacio/Kromeya) Humira adalimumab GP2017 Humira adalimumab BCD-057Humira adalimumab ONS-3010 Humira adalimumab AVT02 Enbrel etanerceptetanercept-szzs Erelzi Enbrel etanercept etanercept-ykro Eticovo Enbreletanercept CT-P05 Enbrel etanercept Benepali Enbrel etanercept AltebrelAvastin bevacizumab bevacizumab-awwb Mvasi Avastin bevacizumabbevacizumab-bvzr Zirabev Avastin bevacizumab AB8 Avastin bevacizumabCT-P16 Solaris eculizumab SB12 Solaris eculizumab ABP 959 Neulastapegfilgrastim pegfilgrastim-jmdb Fulphila Neulasta pegfilgrastimpegfilgrastim-cbqv Udenyca Neulasta pegfilgrastim Pelmeg Neulastapegfilgrastim PF-06881894

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby

Embodiments

-   -   1. A method of treating a condition in a subject in need        thereof, comprising: administering a therapeutically effective        amount of one or more immunosuppressive medications to the        subject, wherein the subject is identified as not having a high        risk of developing progressive multifocal leukoencephalopathy        (PML) by a genetic test.    -   2. A method of treating a condition in a subject in need of        immunosuppressive medication therapy, comprising: administering        a therapeutically effective amount of one or more        immunosuppressive medications to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), wherein the subject's decreased        risk is due to the absence of one or more genetic variations        that occur at a frequency of 10% or less in a population of        human subjects with PML.    -   3. A method of treating a condition in a subject in need of        immunosuppressive medication therapy, comprising: administering        a therapeutically effective amount of one or more        immunosuppressive medications to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), wherein the subject's decreased        risk is due to the absence of one or more genetic variations        that occur at a frequency of more than 10% in a population of        human subjects with PML    -   4. The method of paragraph 1 or 2, wherein the risk is due to        the absence of one or more genetic variations that occur at a        frequency of 10% or less in a population of human subjects with        PML and with an immune deficiency.    -   5. The method of paragraph 1 or 2, wherein the subject's        decreased risk is due to the absence of one or more genetic        variations that occur at a frequency of 10% or less in a        population of human subjects with PML and without an immune        deficiency.    -   6. The method of paragraph 3, wherein the risk is due to the        absence of one or more genetic variations that occur at a        frequency of more than 10% in a population of human subjects        with PML and with an immune deficiency.    -   7. The method of paragraph 3, wherein the subject's decreased        risk is due to the absence of one or more genetic variations        that occur at a frequency of more than 10% in a population of        human subjects with PML and without an immune deficiency.    -   8. A method of treating a condition in a subject in need of        immunosuppressive medication therapy, comprising: administering        a therapeutically effective amount of one or more        immunosuppressive medications to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), and wherein the subject's decreased        risk is due to the absence of one or more genetic variations        that occur at a frequency of 1% or less in a population of human        subjects without PML.    -   9. The method of paragraph 1 or 8, wherein the risk is due to        the absence of one or more genetic variations that occur at a        frequency of 1% or less in a population of human subjects        without PML and with an immune deficiency.    -   10. The method of paragraph 1 or 8, wherein the risk is due to        the absence of one or more genetic variations that occur at a        frequency of 1% or less in a population of human subjects        without PML and without an immune deficiency.    -   11. A method of treating a condition in a subject in need of        immunosuppressive medication therapy, comprising: administering        a therapeutically effective amount of one or more        immunosuppressive medications to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), and wherein the risk is due to the        absence of one or more genetic variations that occur at a        frequency of 10% or less in a population of human subjects with        an immune deficiency.    -   12. The method of paragraph 1 or 11, wherein the risk is due to        the absence of one or more genetic variations that occur at a        frequency of 10% or less in a population of human subjects with        an immune deficiency and with PML.    -   13. The method of paragraph 1 or 11, wherein the risk is due to        the absence of one or more genetic variations that occur at a        frequency of 10% or less in a population of human subjects with        an immune deficiency and without PML.    -   14. A method of treating a condition in a subject in need of        immunosuppressive medication therapy, comprising: administering        a therapeutically effective amount of one or more        immunosuppressive medications to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), and wherein the subject's decreased        risk is due to the absence of one or more genetic variations        that occur at a frequency of 0.1% or less in a population of        human subjects without an immune deficiency.    -   15. The method of paragraph 1 or 14, wherein the risk is due to        the absence of one or more genetic variations that occur at a        frequency of 1% or less in a population of human subjects        without an immune deficiency and with PML.    -   16. The method of paragraph 14, wherein the risk is due to the        absence of one or more genetic variations that occur at a        frequency of 1% or less in a population of human subjects        without an immune deficiency and without PML.    -   17. A method of treating a condition in a subject in need of        immunosuppressive medication therapy, comprising: administering        a therapeutically effective amount of one or more        immunosuppressive medications to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), wherein the subject's decreased        risk is due to the absence of one or more genetic variations in        the subject, wherein the one or more genetic variations have an        odds ratio (OR) of 3 or more, and wherein the OR is:        [DD/DN]/[ND/NN], wherein: DD is the number of subjects in a        diseased cohort of subjects with the one or more genetic        variations; DN the number of subjects in the diseased cohort        without the one or more genetic variations; ND is the number of        subjects in a non-diseased cohort of subjects with the one or        more genetic variations; and NN is the number of subjects in the        non-diseased cohort without the one or more genetic variations.    -   18. The method of paragraph 17, wherein the diseased cohort or        non-diseased cohort comprises at least 100 human subjects.    -   19. The method of paragraph 18, wherein the at least 100 human        subjects comprises        -   (a) at least 10 human subjects with PML,        -   (b) at least 10 human subjects with an immune deficiency,        -   (c) at least 10 human subjects without an immune deficiency,        -   (d) at least 10 human subjects without PML, or        -   (e) any combination thereof.    -   20. The method of any one of paragraphs 2-19, wherein the        subject's decreased risk is due to the absence of one or more        genetic variations that has an odds ratio (OR) of at least 3, 4,        5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 or 50.    -   21. A method of treating a condition in a subject in need of        immunosuppressive medication therapy, comprising: administering        a therapeutically effective amount of one or more        immunosuppressive medications to a subject with a condition,        wherein the subject has a decreased risk of progressive        multifocal leukoencephalopathy (PML) due to an infection of the        brain by John Cunningham virus (JCV), wherein the subject's        decreased risk is due to the presence of gene sequences that do        not comprise any of 2 or more genetic variations in a panel        comprising the 2 or more genetic variations.    -   22. The method of paragraph 21, wherein the 2 or more genetic        variations comprise at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,        13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100 genetic        variations.    -   23. The method of paragraph 21 or 22, wherein the gene sequences        are wild-type gene sequences.    -   24. The method of any one of paragraphs 1 to 23, wherein the        condition is a cancer, an organ transplant, or an autoimmune        disease.    -   25. The method of paragraph 24, wherein the condition is an        autoimmune disease.    -   26. The method of paragraph 25, wherein the autoimmune disease        is selected from the group consisting of Addison disease,        Anti-NMDA receptor encephalitis, antisynthetase syndrome,        Aplastic anemia, autoimmune anemias, Autoimmune hemolytic        anemia, Autoimmune pancreatitis, Behcet's Disease, bullous skin        disorders, Celiac disease-sprue (gluten-sensitive enteropathy),        chronic fatigue syndrome, Chronic inflammatory demyelinating        polyneuropathy, chronic lymphocytic leukemia, Crohn's disease,        Dermatomyositis, Devic's disease, Erythroblastopenia, Evans        syndrome, Focal segmental glomerulosclerosis, Granulomatosis        with polyangiitis, Graves disease, Graves' ophthalmopathy,        Guillain-Barre syndrome, Hashimoto thyroiditis, idiopathic        thrombocytopenic purpura (ITP), IgA nephropathy, IgA-mediated        autoimmune diseases, IgG4-related disease, Inflammatory bowel        disease, Juvenile idiopathic arthritis, Multiple sclerosis,        Myasthenia gravis, myeloma, non-Hodgkin's lymphoma, Opsoclonus        myoclonus syndrome (OMS), Pemphigoid, Pemphigus, pemphigus        vulgaris, Pernicious anemia, polymyositis, Psoriasis, pure red        cell aplasia, Reactive arthritis, Rheumatoid arthritis,        Sarcoidosis, scleroderma, Sjögren syndrome, Systemic lupus        erythematosus, Thrombocytopenic purpura, Thrombotic        thrombocytopenic purpura, Type I diabetes, Ulcerative colitis,        Vasculitis, Vitiligo, and combinations thereof.    -   27. The method of paragraph 26, wherein the autoimmune disease        is multiple sclerosis or Crohn's disease.    -   28. The method of paragraph 27, wherein the autoimmune disease        is multiple sclerosis.    -   29. The method of paragraph 28, wherein the multiple sclerosis        is a relapsing form of multiple sclerosis.    -   30. The method of any one of paragraphs 1 to 29, wherein the one        or more immunosuppressive medications comprise a glucocorticoid,        cytostatic, antibody, drug acting on immunophilins, interferon,        opioid, TNF binding protein, mycophenolate, small biological        agent, small molecule, organic compound, or any combination        thereof.    -   31. The method of any one of paragraphs 1 to 30, wherein the one        or more immunosuppressive medications comprise a glucocorticoid,        cytostatic, antibody, drug acting on immunophilins, interferon,        opioid, TNF binding protein, mycophenolate, small biological        agent, small molecule, organic compound, A2aR antagonist, Akt        inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37        protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40        mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1        agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3        mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional        fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1        and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a        inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor,        FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor        necrosis factor receptor-related gene [GITR] agonist,        glutaminase inhibitor, Human monoclonal antibody against IL-12,        ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist,        MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor,        neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK        inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK        inhibitor, selective sphingosine-1-phosphate receptor modulator,        Src kinase inhibitor, TLR4 agonist, TLR9 agonist, abatacept        (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab,        adrenocorticotropic hormone, agatolimod sodium, AJM300,        aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin        hydrochloride, alvocidib, ambrisentan (e.g. LETAIRIS),        aminocamptothecin, amiselimod, anakinra, andecaliximab,        andrographolides (a botanical medicinal herb also known as        IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib,        asparaginase, atacicept, atezolizumab, avelumab, azacitidine,        azathioprine, bafetinib, baminercept, baricitinib, basiliximab,        becatecarin, begelomab, belatacept, belimumab, bemcentinib,        bendamustine, bendamustine (e.g. bendamustine hydrochloride),        betalutin with lilotomab, bevacizumab, B11B033, B1B059, BIIB061,        bimekizumab, binimetinib, bleomycin, blinatumomab, BNZ-1,        bortezomib (e.g. VELCADE), brentuximab vedotin, bryostatin 1,        bucillamine, buparlisib, busulfan, canakinumab, capecitabine,        carboplatin, carfilzomib, carmustine, cediranib maleate,        cemiplimab, ceralifimod, cerdulatinib, certolizumab (e.g.        certolizumab pegol), cetuximab, chidamide, chlorambucil,        CHS-131, cilengitide, cirmtuzumab, cisplatin, cladribine,        clazakizumab, clemastine, clioquinol, corticosteroids,        cyclophosphamide, cyclosporine, cytarabine, cytotoxic        chemotherapy, daclizumab, dalfampridine (e.g. AMPYRA),        daprolizumab pegol, daratumumab, dasatinib, defactinib,        defibrotide, denosumab, dexamethasone, diacerein, dimethyl        fumarate, dinaciclib, diroximel fumarate (e.g. VUMERITY),        doxorubicin, doxorubicin (e.g. doxorubicin hydrochloride),        durvalumab, duvelisib, duvortuxizumab, eculizumab (e.g.        SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (a neuropeptide        combination of metenkefalin and tridecactide), elezanumab,        elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g.        FUZEON), entinostat, entospletinib, enzastaurin, epacadostat,        epirubicin, epratuzumab, eritoran tetrasodium, etanercept,        etoposide, etrolizumab, everolimus, evobrutinib, filgotinib,        fingolimod (e.g. fingolimod hydrochloride), firategrast,        fludarabine, fluorouracil, fontolizumab, forodesine        hydrochloride, fostamatinib, galunisertib, ganetespib,        ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab,        glasdegib, glassia, glatiramer acetate, glembatumumab vedotin,        glesatinib, golimumab (e.g. SIMPONI), guadecitabine,        hydrocortisone, hydroxychloroquine sulfate, hydroxyurea,        ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin,        idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon,        IMU-838, infliximab, inotuzumab ozogamicin, interferon alfa-2,        interferon beta-1a, interferon beta-1b, interferon gamma-1,        ipilimumab, irofulven, isatuximab, ispinesib, itacitinib,        ixazomib, lapatinib, laquinimod, laromustine, ld-aminopterin,        leflunomide, lenalidomide, lenvatinib, letrozole (e.g. FEMARA),        levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib,        lumiliximab, maraviroc (e.g. SELZENTRY), masitinib,        mavrilimumab, melphalan, mercaptopurine, methotrexate,        methoxsalen, methylprednisone, milatuzumab, mitoxantrone,        mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib        diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate        mofetil (e.g. mycophenolate mofetil hydrochloride), mycophenolic        acid, namilumab, natalizumab, navitoclax, neihulizumab,        nerispirdine, neurovax, niraparib, nivolumab, obatoclax        mesylate, obinutuzumab, oblimersen sodium, ocrelizumab,        ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib,        otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel,        pacritinib, palifermin, panobinostat, pazopanib, peficitinib,        pegfilgrastim (e.g. NEULASTA), peginterferon beta-1a,        pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed,        penclomedine, pentostatin, perifosine, pevonedistat,        pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone,        pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide,        ponatinib, ponesimod, prednisone/prednisolone, pyroxamide,        R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant il-12,        relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir        (e.g. NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246,        sarilumab, secukinumab, selumetinib, simvastatin, sintilimab,        siplizumab, siponimod (e.g. MAYZENT), sirolimus (rapamycin),        sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin        acetate, sunitinib, sunphenon epigallocatechin-gallate,        tabalumab, tacrolimus (e.g. tacrolimus anhydrous), talabostat        mesylate, talacotuzumab, tanespimycin,        tegafur/gimeracil/oteracil, temozolomide, temsirolimus,        tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine,        thiotepa, tipifarnib, tirabrutinib, tislelizumab, tivozanib,        tocilizumab, tofacitinib, TR-14035, tregalizumab, tremelimumab,        treosulfan, ublituximab, umbralisib, upadacitinib, urelumab,        ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib,        veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine        ditartrate, visilizumab, vismodegib, vistusertib, voriconazole        (e.g. VFEND), vorinostat, vosaroxin, ziv-aflibercept, 2B3-201,        3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoic acid,        68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501,        ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494,        ABT-555, ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800,        ACY-1215, AD 452, Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102,        AFX-2, AGEN1884, AGEN2034, AGS67E, AIN457, AK106-001616, ALD518,        ALKS 8700, ALT-803, ALT-803, ALX-0061, ALXN1007, ALXN6000,        AMD3100, AMG 108, AMG 319, AMG 357, AMG 570, AMG 592, AMG 714,        AMG 719, AMG 827, AMP-110, AP1903, APL A12, AP0866, APX005M,        AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797, ARRY-382,        ARRY-438162, ART-I02, ART621, ASK8007, ASN002, ASP015K, ASP1707,        ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188,        ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672,        AZD5991, AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668,        B-701, BAF312, BAY1830839, BBI608, BCD-054, BCD-055, BCD-063,        BCD-089, BCD-100, BCD-132, BCD-145, BEZ235, BG00012, BG9924,        BGB-3111, BGB-A333, BGG492, BHT-3009, BI 655064, BI 695500, BI        695501, BI 836826, BI-1206, BIBR 796 BS, BIIB017, BIIB023,        BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN 673,        BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564,        BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195,        BMS-986205, BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015,        BP001, BT061, BTT-1023, C105, CAL-101, CAM-3001, CAT-8015,        CB-839, CBL0137, CC-1088, CC-115, CC-122, CC-292, CC100,        CCI-779, CCX 354-C, CDKI AT7519, CDP323, CDP6038, CDP870,        CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116, CH-1504,        CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131,        CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO        136, CNTO 148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205,        CR6086, CRx-102, CS-0777, CS1002, CT-011, CT-1530, CT-P10,        CV301, CX-3543, DAC-HYP, DCDT2980S, DI-B4, DPA-714 FDG,        DS-3032b, DT2219ARL, DTRM-505, DTRM-555, DTRMWXHS-12, DWP422,        E6011, E7449, EK-12, ELND002, ENIAl1, EOC202, ETBX-011, F8IL10,        FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327, FPA008, FR104,        FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853, GEH120714,        GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L,        GS-1011, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901,        GSK1223249, GSK1827771, GSK2018682, GSK21110183, GSK239512,        GSK2618960, GSK2831781, GSK2982772, GSK3117391, GSK3152314A,        GSK3196165, GSK3358699, GSK706769, GW-1000-02, GW274150,        GW406381, GW856553, GZ402668, HCD122, HE3286, HL2351, HL237,        hLL1-DOX (IMMU-115), HLXO1, HM71224, HMPL-523, HSC835, HZT-501,        ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125,        INCAGNO2385, INCB018424, INCB028050, INCB039110, INCB047986,        INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145,        IPX056, ISF35, ISIS 104838, ITF2357, JCARH125, JHLI 101, JNJ        38518168, JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001,        JTE-051, JTX-2011, KB003, KD025, KPT-330, KW-2449, KW-2478,        KX2-391, L-778123, LAG525, LAM-002A, LBECO101, LBH589, LFB-R603,        LMB-2, LX3305, LY2127399, LY2189102, LY2439821, LY3009104,        LY3090106, LY3300054, LY3321367, LY3337641, M2951, M7824, M923,        MBG453, MBP8298, MBS2320, MD1003, MDG013, MDV9300, MDX-1100,        MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538, MEDI-551,        MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280,        MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782,        MK0812, MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166,        monoclonal antibody M-T412, monoclonal antibody mono-dgA-RFB4,        MOR00208, MOR103, MORAb-022, MP-435, MP470, MRC375, MRG-106,        MS-533, MSB11022, MSC2490484A, MT-1303, MT-3724, MTIG7192A,        MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071, NIS793, NKTR-214,        NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012,        NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNC0215-0384,        NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32,        ON01910 Na, ONO-2506PO, ONO-4641, ONTAK, OPB 31121, OSI-461,        OTS1671V, P1446A-05, PBF-509, PBR06, PCI 32765, PCI-24781, PD        0360324, PDA001, PDR001, PF-04171327, PF-04236921, PF-04308515,        PF-04629991, PF-05280586, PF-06342674, PF-06410293, PF-06438179,        PF-06650833, PF-06651600, PF-06835375, PG-760564, PH-797804,        PLA-695, PLX3397, PLX5622, POL6326, PRO131921, PR0283698,        PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001, RC18,        REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077,        RGB-03, RGI-2001, RHB-104, RNS60, R05045337, R07123520, Rob 803,        RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409,        SB-681323, SB683699, SBI-087, SC12267 (4SC-101), SCH 727965,        SCIO-469, SD-101, SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302,        SHR1020, SJG-136, SKI-O-703, SMP-114, SNS-032, SNS-062,        SNX-5422, SPARC1103 I, SPC2996, SSR150106, STA 5326 mesylate,        Sunpharma1505, SyB L-0501, Sym022, Sym023, SYN060, T-614, T0001,        TA-650, TAB08, TAK-715, TAK-783, TAK-901, TGR-1202, TH-302,        TL011, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015, TRU-016,        TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R,        VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844,        XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365, and        any combination thereof.    -   32. The method of paragraph 31, wherein the one or more        immunosuppressive medications comprise natalizumab, interferon        beta-1a, interferon beta-1b, glatiramer acetate, peginterferon        beta-1a, teriflunomide, fingolimod, dimethyl fumarate,        alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab,        diroximel fumarate or siponimod, or any combination thereof.    -   33. The method of paragraph 32, wherein the one or more        immunosuppressive medications comprise natalizumab.    -   34. The method of paragraph 33, wherein the natalizumab is        administered via intravenous infusion.    -   35. The method of paragraph 33, wherein about 100 mg to about        500 mg of the natalizumab is administered.    -   36. The method of paragraph 35, wherein about 100 mg to about        500 mg of the natalizumab is administered in four weeks.    -   37. The method of paragraph 35 or 36, wherein about 100 mg to        about 500 mg of the natalizumab is administered via intravenous        infusion in four weeks.    -   38. The method of any one of paragraphs 1 to 37, wherein the        subject does not have one or more genetic variations associated        with a high risk of developing PML.    -   39. The method of any one of paragraphs 1 to 38, wherein the        genetic test comprises detecting one or more genetic variations        associated with a high risk of developing PML in a polynucleic        acid sample from the subject.    -   40. The method of paragraph 38 or 39, wherein the one or more        genetic variations comprise a point mutation, polymorphism,        single nucleotide polymorphism (SNP), single nucleotide        variation (SNV), translocation, insertion, deletion,        amplification, inversion, interstitial deletion, copy number        variation (CNV), structural variation (SV), loss of        heterozygosity, or any combination thereof.    -   41. The method of any one of paragraphs 38 to 40, wherein the        one or more genetic variations disrupt or modulate a        corresponding gene according to Tables 3, 6, 29, 31 and 48.    -   42. A method of treating a condition in a subject in need of        natalizumab therapy, comprising: administering a therapeutically        effective amount of natalizumab to the subject, wherein the        subject is identified as not having one or more genetic        variations that disrupt or modulate a corresponding gene        according to Tables 3, 6, 29, 31 and 48.    -   43. A method of reducing a risk of a subject developing        progressive multifocal leukoencephalopathy (PML) comprising        administering a therapeutically effective amount of natalizumab        to the subject, wherein the subject is identified as not having        one or more genetic variations that disrupt or modulate a        corresponding gene according to Tables 3, 6, 29, 31 and 48.    -   44. The method of paragraph 42 or 43, wherein the condition is        multiple sclerosis.    -   45. The method of paragraph 42 or 43, wherein the condition is        Crohn's disease.    -   46. A method of treating multiple sclerosis comprising        administering natalizumab to a subject with multiple sclerosis,        wherein the subject is identified as not having one or more        genetic variations that disrupt or modulate a corresponding gene        according to Tables 3, 6, 29, 31 and 48.    -   47. A method of treating Crohn's disease comprising        administering natalizumab to a subject with Crohn's disease,        wherein the subject is identified as not having one or more        genetic variations that disrupt or modulate a corresponding gene        according to Tables 3, 6, 29, 31 and 48.    -   48. A method of treating multiple sclerosis comprising        -   (a) testing a subject with multiple sclerosis for the            presence of one or more genetic variations that disrupt or            modulate a corresponding gene according to Tables 3, 6, 29,            31 and 48,        -   (b) determining that the subject does not have the one or            more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48,            and        -   (c) administering natalizumab to the subject that was            determined not to have the one or more genetic variations            that disrupt or modulate a corresponding gene according to            Tables 3, 6, 29, 31 and 48.    -   49. A method of treating Crohn's disease comprising        -   (a) testing a subject with Crohn's disease for the presence            of one or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48,        -   (b) determining that the subject does not have the one or            more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48,            and        -   (c) administering natalizumab to the subject that was            determined not to have the one or more genetic variations            that disrupt or modulate a corresponding gene according to            Tables 3, 6, 29, 31 and 48.    -   50. A method of reducing a risk of a subject developing        progressive multifocal leukoencephalopathy (PML) comprising        -   (a) testing a subject for the presence of one or more            genetic variations that disrupt or modulate a corresponding            gene according to Tables 3, 6, 29, 31 and 48,        -   (b) determining that the subject has at least one of the one            or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48,            and        -   (c) advising against administering natalizumab to the            subject that was determined to have at least one of the one            or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48.    -   51. The method of paragraph 50, wherein the subject has multiple        sclerosis.    -   52. The method of paragraph 50, wherein the subject has Crohn's        disease.    -   53. A method of treating multiple sclerosis comprising        -   (a) testing a subject with multiple sclerosis for the            presence of one or more genetic variations that disrupt or            modulate a corresponding gene according to Tables 3, 6, 29,            31 and 48,        -   (b) determining that the subject has at least one of the one            or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48,            and        -   (c) advising against administering natalizumab to the            subject that was determined to have at least one of the one            or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48.    -   54. A method of treating Crohn's disease comprising        -   (a) testing a subject with Crohn's disease for the presence            of one or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48,        -   (b) determining that the subject has at least one of the one            or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48,            and        -   (c) advising against administering natalizumab to the            subject that was determined to have at least one of the one            or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48.    -   55. The method of any one of paragraphs 50 to 54, wherein the        advising comprises advising that administering natalizumab is        contraindicated.    -   56. The method of any one of paragraphs 50 to 55, wherein the        advising comprises advising that administering natalizumab        increases the risk of the subject developing progressive        multifocal leukoencephalopathy (PML).    -   57. The method of any one of paragraphs 50 to 56, wherein the        advising comprises advising that administering natalizumab is a        factor that increases the risk of the subject developing        progressive multifocal leukoencephalopathy (PML).    -   58. The method of any one of paragraphs 42 to 57, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene according to Table 13.    -   59. The method of any one of paragraphs 42 to 57, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene according to Table 14.    -   60. The method of any one of paragraphs 42 to 57, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene according to Table 15.    -   61. The method of any one of paragraphs 42 to 57, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene according to Table 16.    -   62. The method of any one of paragraphs 42 to 57, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene according to Table 17.    -   63. The method of any one of paragraphs 42 to 57, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene according to Table 18.    -   64. The method of any one of paragraphs 42 to 63, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of ALG12, AP3B1, ASHIL,        ATL2, ATM, ATR, BACH1, BLM, CHD7, CLCN7, CR2, CX3CR1, DOCK2,        DOCK8, EHF, EPG5, FAS, FUK, GFI1, GOLGB1, GTPBP4, HIVEP1,        HIVEP2, HIVEP3, IFIH1, IGLL1, IL10, IL12B, IL17F, ITK, ITSN2,        JAGN1, KITLG, LRBA, LYST, MALT1, MAVS, MCEE, NHEJ1, NOD2, NRIP1,        ORAI1, PGM3, PIK3CD, PLCG2, PNP, POLE, PRF1, RBCK1, RBFOX1,        RNASEL, RTEL1, SALL2, SHARPIN, SNAP29, STIM2, STXBP2, TAP1,        TBC1D16, TCIRG1, TICAM1, TMEM173, TNFRSF10A, TTC7A, VPS13B, and        combinations thereof.    -   65. The method of any one of paragraphs 42 to 63, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of ACD, ADGRL2, AIRE,        ATG5, ATG7, BLK, BRD4, C3, C7, C8A, C8B, C9, CAMLG, CCBE1, CCZ1,        CD22, CD36, CD37, CD5, CD72, CFH, CFHR1, CFHR2, CFHR3, CFHR4,        CFHR5, CFTR, CHD2, CLEC16A, CLPB, COPA, CTC1, DNAJC21, EGF,        ERCC6L2, FAT4, FCER2, HERC5, HERC6, ICAM1, IF135, IFIT1, IFIT3,        IL4, ITSN1, KMT2D, KRAS, LRRK2, MASP2, MBL2, MCM5, MDC1, MFN2,        MLH1, MMP9, MOGS, MON1A, MON1B, MSH2, MSH5, MX1, MX2, MYSM1,        NBAS, NCF1, NCF2, NCF4, NFAT5, NLRP2, NLRX1, NOD1, OAS1, OAS2,        OAS3, ORC4, PARN, PEPD, PINK1, PLAU, PLAUR, PLCG1, PLD1,        PLEKHM1, PLK1, PLXNB1, PRRC2A, RAB5A, RAB5B, RAD50, RANBP2,        RELA, RLTPR, RNF125, RPSA, RSAD2, SAMD9, SAMD9L, SERPINA1,        SERPINB2, SMARCAL1, SMURF2, SRP54, TBCID17, TCN2, TEK, TFPI,        TMC8, TP53AIP1, TRAF3IP2, USB1, USP3, VEGFA, WASHC5, WRAP53, and        XAF1.    -   66. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PLCG2, RBCK1, EPG5,        IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2,        NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2,        ALG12, and combinations thereof.    -   67. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PLCG2, IFIH1, TCIRG1,        IGLL1, MAVS, SHARPIN, CHD7, CX3CR1, LRBA, HIVEP3, RNASEL, and        combinations thereof.    -   68. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of SHARPIN, RTEL1, PGM3,        TMEM173, CLCN7, MAVS, ORAI1, RBFOX1, MALT1, GFI1, DOCK2, ATM,        SNAP29, TICAM1, GTPBP4, BACH1, STXBP2, FAS, GOLGB1, FUK, IL10,        ITK, STIM2, ASH1L, TBCID16, LYST, SALL2, CHD7, BLM, NOD2, IGLL1,        TTC7A, KITLG, ATR, ATM, CR2, HIVEP2, ITSN2, DOCK8, VPS13B,        NRIP1, and combinations thereof.    -   69. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of SHARPIN, IFIH1,        PLCG2, CHD7, and combinations thereof.    -   70. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PLCG2, POLE, LRBA,        EPG5, SHARPIN, and combinations thereof.    -   71. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PKHD1, LY9, CFHR2,        NQO2, AIRE, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2, PLCG2, TAP1,        GFI1, IGLL1, MCM5, IFIH1, FCN3 and SERPINA1.    -   72. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of LY9, PKHD1, AIRE,        CFHR2, NQO2, IGLL1, PRAM1, MDC1, FCN2, STXBP2, TCIRG1 and PLCG2.    -   73. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of LIG1, MCM5, GF11,        IFIH1, IGLL1, ATM, TAP1, FCN3, LRBA and SERPINA1.    -   74. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of TAP1, GFI1, IGLL1,        MCM5, IFIH1, FCN3, SERPINA1.    -   75. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PKHD1, LY9, CFHR2,        NQO2, AIRE, IGLL1, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2 and        PLCG2.    -   76. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of LY9, LIG1, PKHD1,        AIRE, GFI1, CFHR2, NQO2, PRAM1, C8B, DNASE1L3, PLCG2, HIVEP3 and        TCIRG1.    -   77. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PRAM1, HIVEP3 and        TCIRG1.    -   78. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of LY9, LIG1, PKHD1,        AIRE, GFI1, CFHR2, NQO2, C8B, DNASE1L3 and PLCG2.    -   79. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of IGLL1, MDC1, STXBP2,        PRAM1, ATM, FCN2, IGLL1, MCM5, IFIH1, TAP1, PLCG2, FCN3, DNER,        SERPINA1 and LRBA.    -   80. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PRAM1, ATM, TAP1,        PLCG2, FCN3, DNER, SERPINA1 and LRBA.    -   81. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of IGLL1, MDC1, STXBP2,        FCN2, IGLL1, MCM5 and IFIH1.    -   82. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting ofAIRE, ATM, C8B, CFHR2,        DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IFIH1, IGLL1, LIG1,        LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PLCG2, PRAM1, SERPINA1,        STXBP2, TAP1 and TCIRG1.    -   83. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting ofAIRE, ATM, C8B, CFHR2,        DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IGLL1, LIG1, LRBA,        LY9, MCM5, MDC1, NQO2, PKHD1, PRAM1, SERPINA1, and TAP1.    -   84. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of FCN2, LY9 and PRAM1.    -   85. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PLCG2, RBCK1, EPG5,        IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2,        NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2,        ALG12, FCN2, LY9 and PRAM1.    -   86. The method of any one of paragraphs 42 to 64, wherein the        testing comprises testing the subject for the presence of one or        more genetic variations that disrupt or modulate a corresponding        gene selected from the group consisting of PLCG2, CHD7, IFIH1,        AP3B1, EPG5, PIK3CD, LRBA, SHARPIN, and combinations thereof.    -   87. The method of any one of paragraphs 42 to 86, wherein the        subject is identified as not having a high risk of developing        progressive multifocal leukoencephalopathy (PML) by a genetic        test.    -   88. The method of any one of paragraphs 48 to 87, wherein the        testing comprises assaying a polynucleic acid sample from the        subject for the one or more genetic variations.    -   89. The method of any one of paragraphs 38 to 88, wherein the        one or more genetic variations result in a loss of function of        the corresponding gene.    -   90. The method of any one of paragraphs 41 to 89, wherein the        corresponding gene comprises a gene selected from the group        consisting of gene numbers (GNs) GN1-GN765.    -   91. The method of paragraph 90, wherein the corresponding gene        comprises a gene selected from the group consisting of gene        numbers (GNs) GN1-GN156 in Table 3.    -   92. The method of paragraph 90, wherein the corresponding gene        comprises a gene selected from the group consisting of gene        numbers (GNs) GN 2-4, 6, 8-13, 23-28, 31-39, 41-47, 51-57,        59-62, 64-67, 69, 72-75, 89, 92-95, 98-105, 107-120, 123-128,        130, 131, 133, 134, 136, 138-142, 145, 147, 148, 157-174,        176-179, 181-205, 207-239, 241, 243-307, 309-315, 317-353,        355-369, 371-435, 437, 439-482 and 484-490 in Table 6.    -   93. The method of paragraph 90, wherein the corresponding gene        comprises a gene selected from the group consisting of gene        numbers (GNs) GN491-GN492 in Table 29.    -   94. The method of paragraph 90, wherein the corresponding gene        comprises a gene selected from the group consisting of gene        numbers (GNs) GN493-GN762 in Table 31.    -   95. The method of paragraph 90, wherein the corresponding gene        comprises a gene selected from the group consisting of gene        numbers (GNs) GN763-GN765 in Table 48.    -   96. The method of paragraph 90, wherein the corresponding gene        comprises a gene selected from Tables 34-40, 42, 45A, 45B, 45C,        48, 50A, 50B and 51-62.    -   97. The method of paragraph 90, wherein the corresponding gene        comprises a gene selected from the group consisting of PLCG2,        RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF,        IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP,        MCEE, DOCK2 and ALG12.    -   98. The method of any one of paragraphs 38 to 97, wherein the        one or more genetic variations are encoded by a sequence with at        least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to SEQ ID NOs 1-172 or        SRN1-SRN363, with 100% sequence identity to SEQ ID NOs        1000-1329, or with at least 80% and less than 100% sequence        identity to GN1-GN490, or complements thereof.    -   99. The method of any one of paragraphs 38 to 97, wherein the        one or more genetic variations are encoded by a sequence with at        least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to SEQ ID NOs 1-172,        2200-2203 or SRN1-SRN366, with 100% sequence identity to SEQ ID        NOs 1000-1329, 3000-3274, or with at least 80% and less than        100% sequence identity to GN1-GN765, or complements thereof.    -   100. The method of any one of paragraphs 38 to 97, wherein the        one or more genetic variations are encoded by a sequence with at        least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203        or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs        3000-3274, or with at least 80% and less than 100% sequence        identity to GN491-GN765, or complements thereof.    -   101. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a CNV with at        least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to SEQ ID NOs 1-172, or        complements thereof.    -   102. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a CNV with at        least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203,        or complements thereof.    -   103. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a CNV        sub-region (SRN) with at least 60%, at least 70%, at least 80%,        at least 90%, at least 95%, or at least 99% sequence identity to        SRN1-SRN363, or complements thereof.    -   104. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a CNV        sub-region (SRN) with at least 60%, at least 70%, at least 80%,        at least 90%, at least 95%, or at least 99% sequence identity to        SRN364-SRN366, or complements thereof.    -   105. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a single        nucleotide variation (SNV) with a sequence of any one of SEQ ID        NOs: 1000-1329, or complements thereof.    -   106. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a single        nucleotide variation (SNV) with a sequence of any one of SEQ ID        NOs: 3000-3274, or complements thereof.    -   107. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a sequence        with at least 80% and less than 100% sequence identity to        GN1-GN490, or complements thereof.    -   108. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a sequence        with at least 80% and less than 100% sequence identity to        GN491-GN765, or complements thereof.    -   109. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a single        nucleotide variation (SNV) with a sequence of any one of SEQ ID        NO: 1000, 1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016, 1017,        1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037, 1040,        1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062,        1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076,        1077, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100,        1101, 1104, 1107, 1114, 1116, 1118, 121, 122, 1123, 125, 1126,        1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136, 1137, 1138,        1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157, 1160, 1161,        1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176, 1177,        1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200,        1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226,        1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239, 1247, 1248,        1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259, 1260, 1261,        1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283, 1284, 1286,        1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311, 1327 or        1328, or complements thereof.    -   110. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a single        nucleotide variation (SNV) with a sequence of any one of SEQ ID        NO: 3000-3274, or complements thereof.    -   111. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation encoded by a single        nucleotide variation (SNV) with a sequence of any one of SEQ ID        NO: 3300-3351, 3400-3467 or 3500-3526.    -   112. The method of paragraph 109, wherein the one or more        genetic variations comprise a genetic variation encoded by a        single nucleotide variation (SNV) with a sequence of any one of        SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056,        1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135,        1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184,        1193, 1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255,        1256, 1259, 1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287,        1289, 1299 or 1311, or complements thereof.    -   113. The method of paragraph 109, wherein the one or more        genetic variations comprise a genetic variation encoded by a        single nucleotide variation (SNV) with a sequence of any one of        SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017,        1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059,        1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076,        1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104,        1107, 1116, 1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133,        1136, 1137, 1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165,        1166, 1168, 1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180,        1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226,        1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250,        1251, 1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286,        1290, 1291, 1300, 1301, 1304, 1327 or 1328, or complements        thereof.    -   114. The method of paragraph 98, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr16:81942175 A>G, chr2:163136505 C>G,        chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T,        chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C,        chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,        chr1:182554557 C>T, chr8:145154824 A>C, chr20:62305450 C>T,        chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,        chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,        chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,        chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,        chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A,        chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C,        chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,        chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,        chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,        chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,        chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,        chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,        chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T,        chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A,        chr21:16339852 T>C, and any combination thereof, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   115. The method of paragraph 114, wherein the one or more        genetic variations comprise a genetic variation selected from        the group consisting of chr16:81942175 A>G, chr2:163136505 C>G,        chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T,        chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C,        chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,        chr1:182554557 C>T, and any combination thereof, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   116. The method of paragraph 114, wherein the one or more        genetic variations comprise a genetic variation selected from        the group consisting of chr8:145154824 A>C, chr20:62305450 C>T,        chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,        chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,        chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,        chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,        chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A,        chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C,        chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,        chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,        chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,        chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,        chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,        chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,        chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T,        chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A,        chr21:16339852 T>C, and any combination thereof, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   117. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr1:196759282, C>T, chr4:126412634, C>G,        chr10:75673748, A>C, chr6:30675830, T>A, chr6:30680721, G>A,        chr12:56385915, GGGA>G, chr18:57103126, G>A, chr3:171321023,        C>T, chr1:59131311, G>T, chr22:31008867, T>C, chr2:74690378,        C>T, chr17:7592168, C>G, chr2:74690039, G>A, chr12:113448288,        A>G, chr17:76130947, G>T, chr2:15674686, T>C, chr2:15607842,        T>C, chr14:94847262, T>A, chr4:126412154, G>A, chr22:37271882,        T>C, chr20:44640959, G>A, chr17:8138569, C>G, chr12:113357237,        G>C, chr12:113357209, G>A, chr11:60893235, C>T, chr12:113357442,        G>A, chr5:40964852, A>C, chr14:35497285, T>C, chr19:55494157,        G>A, and any combination thereof, wherein chromosome positions        of the one or more genetic variations are defined with respect        to UCSC hg19.    -   118. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr11:72145307, C>G, chr7:30491421, G>T,        chr6:30673403, A>G, chr19:44153248, T>C, chr17:43555253, A>G,        chr2:188349523, A>G, chr1:57409459, C>A, chr4:126241248, C>G,        chr5:39311336, A>T, chr17:76129619, C>T, chr4:110929301, T>C,        chr3:11402163, G>A, chr16:67694044, C>T, chr19:10395141, G>A,        chr6:106740989, T>C, chr1:183532364, T>A, chr22:35806756, G>A,        chr4:110865044, G>C, chr4:110864533, C>T, chr4:126238090, G>T,        chr4:110932508, C>A, chr6:31605016, T>C, chr7:92733766, C>A,        chr18:29645930, A>T, and any combination thereof, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   119. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr21:45708278, G>A, chr11:108106443, T>A,        chr1:57409459, C>A, chr1:196918605, A>G, chr3:58191230, G>T,        chr2:230579019, G>A, chr9:137779251, G>A, chr1:27699670, AG>A,        chr1:92946625, G>C, chr1:42047208, C>G, chr2:163136505, C>G,        chr22:23915583, T>C, chr22:23915745, G>A, chr19:48643270, C>T,        chr4:151793903, T>C, chr1:160769595, AG>A, chr22:35806756, G>A,        chr6:30673359, T>G, chr6:3015818, G>A, chr6:51798908, C>T,        chr16:81942175, A>G, chr19:8564523, T>G, chr14:94847262, T>A,        chr19:7712287, G>C, chr6:32814942, C>T, chr6:32816772, C>A and        chr11:67818269, G>A, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   120. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr21:45708278, G>A, chr11:108106443, T>A,        chr1:57409459, C>A, chr1:196918605, A>G, chr3:58191230, G>T,        chr2:230579019, G>A, chr9:137779251, G>A, chr1:27699670, AG>A,        chr1:92946625, G>C, chr1:42047208, C>G, chr22:23915583, T>C,        chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A,        chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A,        chr6:51798908, C>T, chr19:8564523, T>G, chr14:94847262, T>A,        chr6:32814942, C>T and chr6:32816772, C>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   121. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr22:23915745, G>A, chr6:30673359, T>G,        chr19:7712287, G>C, chr9:137779251, G>A, chr22:23915583, T>C,        chr22:35806756, G>A and chr2:163136505, C>G, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   122. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr19:8564523, T>G, chr11:108106443, T>A,        chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G,        chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262, T>A        and chr4:151793903, T>C, wherein chromosome positions of the one        or more genetic variations are defined with respect to UCSC        hg19.    -   123. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr22:23915745, G>A, chr6:30673359, T>G,        chr19:7712287, G>C, chr19:8564523, T>G, chr11:108106443, T>A,        chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A,        chr2:163136505, C>G, chr6:32816772, C>A, chr6:32814942, C>T,        chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A,        chr14:94847262 and T>A, chr4:151793903, T>C, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   124. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr1:160769595, AG>A, chr19:48643270, C>T,        chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C,        chr1:196918605, A>G, chr6:3015818, G>A, chr1:57409459, C>A,        chr3:58191230, G>T and chr16:81942175, A>G, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   125. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr19:8564523, T>G, chr1:42047208, C>G and        chr11:67818269, G>A, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   126. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr1:160769595, AG>A, chr19:48643270, C>T,        chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C,        chr1:196918605, A>G, chr6:3015818, G>A, chr19:8564523, T>G,        chr1:57409459, C>A, chr3:58191230, G>T, chr16:81942175, A>G,        chr1:42047208, C>G and chr11:67818269, G>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   127. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr6:51798908, C>T, chr1:160769595, AG>A,        chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A,        chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A,        chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A,        chr19:7712287, G>C and chr16:81942175, A>G, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   128. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr6:32816772, C>A, chr6:32814942, C>T,        chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A,        chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262,        T>A, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   129. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr6:51798908, C>T, chr1:160769595, AG>A,        chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A,        chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A,        chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A,        chr19:7712287, G>C, chr16:81942175, A>G, chr6:32816772, C>A,        chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C,        chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A        and chr14:94847262, T>A, wherein chromosome positions of the one        or more genetic variations are defined with respect to UCSC        hg19.    -   130. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr1:160769595, AG>A, chr6:51798908, C>T,        chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A,        chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G,        chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A and        chr16:81942175, A>G, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   131. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr19:48643270, C>T, chr22:35806756, G>A,        chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C,        chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A,        chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262,        T>A, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   132. The method of paragraph 99, wherein the one or more genetic        variations comprise a genetic variation selected from the group        consisting of chr1:160769595, AG>A, chr6:51798908, C>T,        chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A,        chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G,        chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A,        chr16:81942175, A>G, chr19:48643270, C>T, chr22:35806756, G>A,        chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C,        chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A,        chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262,        T>A, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   133. The method of paragraph 99, wherein the one or more genetic        variations do not comprise a genetic variation of        chr2:163136505, C>G, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   134. The method of paragraph 99, wherein the one or more genetic        variations do not comprise a genetic variation of        chr22:23915745, G>A, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   135. The method of paragraph 99, wherein the one or more genetic        variations do not comprise a genetic variation of        chr16:81942175, A>G, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   136. The method of paragraph 99, wherein the one or more genetic        variations do not comprise a genetic variation of chr19:7712287,        G>C, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   137. The method of paragraph 99, wherein the one or more genetic        variations do not comprise a genetic variation of        chr11:67818269, G>A, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   138. The method of paragraph 99, wherein the one or more genetic        variations do not comprise a genetic variation of        chr2:163136505, C>G; chr22:23915745, G>A; chr16:81942175, A>G;        chr19:7712287, G>C; and chr11:67818269, G>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   139. The method of any one of paragraphs 105 or 109-138, wherein        the SNV is a heterozygous SNV.    -   140. The method of any one of paragraphs 105 or 109-138, wherein        the SNV is a homozygous SNV.    -   141. The method of paragraph 98, wherein the one or more genetic        variations comprise a pair of single nucleotide variations        (SNVs), wherein the pair of SNVs are encoded by any one of SEQ        ID NO pairs: 1003 and 1004, 1003 and 1005, 1006 and 1007, 1024        and 1025, 1030 and 1031, 1047 and 1048, 1049 and 1050, 1063 and        1064, 1063 and 1065, 1063 and 1066, 1075 and 1076, 1091 and        1093, 1091 and 1096, 1093 and 1095, 1094 and 1097, 1098 and        1099, 1098 and 1100, 1099 and 1100, 1102 and 1103, 1104 and        1106, 1104 and 1107, 1104 and 1108, 1104 and 1109, 1104 and        1110, 1104 and 1111, 1104 and 1112, 1110 and 1111, 1112 and        1113, 1119 and 1120, 1124 and 1125, 1124 and 1126, 1125 and        1126, 1140 and 1141, 1142 and 1144, 1146 and 1151, 1147 and        1148, 1147 and 1149, 1153 and 1146, 1153 and 1147, 1155 and        1156, 1160 and 1161, 1165 and 1166, 1186 and 1187, 1188 and        1193, 1189 and 1193, 1191 and 1192, 1191 and 1193, 1191 and        1195, 1192 and 1193, 1192 and 1195, 1196 and 1197, 1206 and        1207, 1210 and 1218, 1211 and 1213, 1212 and 1213, 1213 and        1215, 1213 and 1216, 1213 and 1217, 1233 and 1238, 1242 and        1243, 1245 and 1246, 1263 and 1260, 1269 and 1279, 1270 and        1279, 1270 and 1282, 1271 and 1279, 1274 and 1279, 1278 and        1279, 1278 and 1281, 1279 and 1280, 1279 and 1281, 1279 and        1282, 1292 and 1293, 1296 and 1297, 1305 and 1314, 1306 and        1310, 1313 and 1321 or 1315 and 1322, or complements thereof.    -   142. The method of paragraph 98, wherein the one or more genetic        variations comprise a genetic variation encoded by a CNV with at        least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to any one of SEQ ID NOs        157, 2, 140, 65, 26, 14 or 45, or complements thereof.    -   143. The method of paragraph 142, wherein the one or more        genetic variations comprise a genetic variation encoded by a CNV        with at least 60%, at least 70%, at least 80%, at least 90%, at        least 95%, or at least 99% sequence identity to any one of SEQ        ID NOs 2, 140, 65, 26, 14 or 45, or complements thereof.    -   144. The method of paragraph 142, wherein the one or more        genetic variations comprise a genetic variation encoded by a CNV        with at least 60%, at least 70%, at least 80%, at least 90%, at        least 95%, or at least 99% sequence identity to SEQ ID NO 157,        or a complement thereof    -   145. The method of paragraph 98, wherein the one or more genetic        variations comprise a CNV-SNV pair comprising a CNV and a single        nucleotide variation (SNV), wherein the SNV of the CNV-SNV pair        is encoded by any one of SEQ ID NO pairs: 146 and 1301, 85 and        1173, 58 and 1107, 58 and 1104, 91 and 1199, 103 and 1225, 103        and 1086 or 41 and 1223, or complements thereof.    -   146. The method of any one of paragraphs 38 to 145, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of: chr8:145154222 G>A,        chr2:163136505 C>G, chr116:81942175 A>G, chr8:61654298 T>A, and        combinations thereof.    -   147. The method of any one of paragraphs 38 to 145, wherein the        one or more genetic variations disrupt or modulate one or more        of the following genes: PLCG2, POLE, LRBA, EPG5 and SHARPIN.    -   148. The method of any one of paragraphs 38 to 145, wherein the        one or more genetic variations disrupt or modulate one or more        of the following genes: PLCG2, CHD7, IFIH1, AP3B1, EPG5, PIK3CD,        LRBA and SHARPIN.    -   149. The method of any one of paragraphs 41 to 148, wherein the        corresponding gene encodes a transcript with a sequence that has        at least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to any one of SEQ ID NOs        173-455, 1500-2177, 2204-2215, 2300-2893, or complements        thereof.    -   150. The method of paragraph 149, wherein the corresponding gene        encodes a transcript with a sequence that has at least 60%, at        least 70%, at least 80%, at least 90%, at least 95%, or at least        99% sequence identity to any one of SEQ ID NOs 173-455, or        complements thereof.    -   151. The method of paragraph 149, wherein the corresponding gene        encodes a transcript with a sequence that has at least 60%, at        least 70%, at least 80%, at least 90%, at least 95%, or at least        99% sequence identity to any one of SEQ ID NOs 1500-2177, or        complements thereof.    -   152. The method of paragraph 149, wherein the corresponding gene        encodes a transcript with a sequence that has at least 60%, at        least 70%, at least 80%, at least 90%, at least 95%, or at least        99% sequence identity to any one of SEQ ID NOs 2204-2215, or        complements thereof.    -   153. The method of paragraph 149, wherein the corresponding gene        encodes a transcript with a sequence that has at least 60%, at        least 70%, at least 80%, at least 90%, at least 95%, or at least        99% sequence identity to any one of SEQ ID NOs 2300-2893, or        complements thereof.    -   154. The method of any one of paragraphs 38 to 151, wherein the        one or more genetic variations comprise 2 or 3 or 4 or 5 or more        genetic variations.    -   155. The method of paragraph 154, wherein the one or more        genetic variations comprise 10 or more genetic variations.    -   156. The method of paragraph 154, wherein the one or more        genetic variations comprise 20 or more genetic variations.    -   157. The method of paragraph 154, wherein the one or more        genetic variations comprise 50 or more genetic variations.    -   158. The method of any one of paragraphs 1 to 41 and 87 to 157,        wherein the genetic test or the testing comprises microarray        analysis, PCR, sequencing, nucleic acid hybridization, or any        combination thereof.    -   159. The method of paragraph 158, wherein the genetic test or        the testing comprises microarray analysis selected from the        group consisting of a Comparative Genomic Hybridization (CGH)        array analysis and an SNP array analysis.    -   160. The method of paragraph 158 or 159, wherein the genetic        test or the testing comprises sequencing, wherein the sequencing        is selected from the group consisting of Massively Parallel        Signature Sequencing (MPSS), polony sequencing, 454        pyrosequencing, Illumina sequencing, Illumina (Solexa)        sequencing using 10× Genomics library preparation, SOLiD        sequencing, ion semiconductor sequencing, DNA nanoball        sequencing, heliscope single molecule sequencing, single        molecule real time (SMRT) sequencing, RNAP sequencing, Nanopore        DNA sequencing, sequencing by hybridization, and microfluidic        Sanger sequencing.    -   161. The method of any one of paragraphs 1 to 41 and 87 to 160,        wherein the genetic test or the testing comprises analyzing a        whole genome of the subject.    -   162. The method of any one of paragraphs 1 to 41 and 87 to 161,        wherein the genetic test or the testing comprises analyzing a        whole exome of the subject.    -   163. The method of any one of paragraphs 1 to 41 and 87 to 160,        wherein the genetic test or the testing comprises analyzing        nucleic acid information that has already been obtained for a        whole genome or a whole exome of the subject.    -   164. The method of paragraph 163, wherein the nucleic acid        information is obtained from an in silico analysis.    -   165. The method of any one of paragraphs 1 to 164, wherein the        subject is a human subject.    -   166. The method of any one of paragraphs 39 to 41 and 88 to 165,        wherein the polynucleic acid sample comprises a polynucleic acid        from blood, saliva, urine, serum, tears, skin, tissue, or hair        of the subject.    -   167. The method of any one of paragraphs 1 to 166, wherein the        method further comprises treating the subject with an agent that        reduces a viral load in the subject.    -   168. The method of paragraph 167, wherein the immunosuppressive        agent is administered after the viral load is reduced.    -   169. The method of paragraph 167 or 168, wherein the viral load        is a JCV viral load.    -   170. The method of any one of paragraphs 167 to 169, wherein the        agent that reduces the viral load is an agent that targets JCV.    -   171. The method of any one of paragraphs 1 to 170, wherein the        method further comprises analyzing for a presence of JCV in a        biological sample from the subject.    -   172. The method of paragraph 171, wherein the analyzing for a        presence of JCV comprises contacting a JCV detection reagent to        the biological sample.    -   173. The method of paragraph 172, wherein the JCV detection        reagent is selected from the group consisting of an anti-JCV        antibody, a JCV specific primer, and combinations thereof.    -   174. A method of treating a condition in a subject in need        thereof, comprising: administering        -   (a) a therapeutically effective amount of one or more            immunosuppressive medications to the subject, and        -   (b) one or more agents that reduce a viral load in the            subject, wherein the subject is identified as not having a            high risk of developing progressive multifocal            leukoencephalopathy (PML) by a genetic test.    -   175. A method of treating a condition in a subject in need        thereof, comprising:        -   (a) analyzing a polynucleic acid sample from the subject for            one or more genetic variations that disrupt or modulate a            gene of GN1-GN765, wherein a genetic variation of the one or            more genetic variations that disrupt or modulate a gene of            GN1-GN765 is not present in the polynucleic acid sample;        -   (b) identifying the subject as not having a high risk of            developing PML;        -   (c) administering a therapeutically effective amount of one            or more immunosuppressive medications to the subject.    -   176. A method of identifying a subject as having a risk of        developing PML, comprising:        -   (a) analyzing a polynucleic acid sample from the subject for            one or more genetic variations that disrupt or modulate a            gene of GN1-GN765, wherein a genetic variation of the one or            more genetic variations that disrupt or modulate a gene of            GN1-GN765 is not present in the polynucleic acid sample;        -   (b) identifying the subject as not having a high risk of            developing PML.    -   177. A method of identifying a subject as having a risk of        developing progressive multifocal leukoencephalopathy (PML)        comprising        -   (a) obtaining a genetic test result from a polynucleic acid            sample from a subject, and        -   (b) identifying the subject as having a risk of developing            PML based on the genetic test result;            wherein the subject is immunosuppressed.    -   178. A method of monitoring a subject as having a risk of        developing progressive multifocal leukoencephalopathy (PML)        comprising        -   (a) obtaining a genetic test result from a polynucleic acid            sample from a subject, and        -   (b) identifying the subject as having an increased risk of            developing PML based on the genetic test result;            wherein the subject is immunosuppressed.    -   179. The method of paragraph 178, wherein the subject is on an        immunosuppressive therapy.    -   180. A method of identifying a subject as having a risk of        developing progressive multifocal leukoencephalopathy (PML)        comprising        -   (a) detecting one or more genetic variations that disrupt or            modulate a gene of GN1-GN765 in a polynucleic acid sample            from a subject, and        -   (b) identifying the subject as having a risk of developing            PML;            wherein the subject is immunosuppressed.    -   181. A method of identifying a subject as having a risk of        developing progressive multifocal leukoencephalopathy (PML)        comprising:        -   (a) analyzing a polynucleic acid sample from the subject for            one or more genetic variations that disrupt or modulate a            gene of GN1-GN765, wherein a genetic variation of the one or            more genetic variations that disrupt or modulate a gene of            GN1-GN765 is present in the polynucleic acid sample;    -   (b) identifying the subject as having a high risk of developing        PML;        wherein the subject is immunosuppressed.    -   182. The method of any one of paragraphs 177 to 181, wherein the        subject has HIV.    -   183. The method of any one of paragraphs 175 to 182, wherein the        condition is a cancer, an organ transplant, or an autoimmune        disease.    -   184. The method of paragraph 183, wherein the condition is an        autoimmune disease.    -   185. The method of paragraph 184, wherein the autoimmune disease        is selected from the group consisting of Addison disease,        Behcet's Disease, Inflammatory bowel disease, Celiac        disease-sprue (gluten-sensitive enteropathy), Crohn's disease,        Dermatomyositis, Focal segmental glomerulosclerosis, Graves        disease, Hashimoto thyroiditis, Multiple sclerosis, Myasthenia        gravis, Pemphigus, Pemphigoid, Aplastic anemia, Pernicious        anemia, Autoimmune hemolytic anemia, Erythroblastopenia,        Thrombocytopenic purpura, Evans syndrome, Vasculitis,        Granulomatosis with polyangiitis, Chronic inflammatory        demyelinating polyneuropathy, Guillain-Barre syndrome, Anti-NMDA        receptor encephalitis, Devic's disease, Autoimmune pancreatitis,        Opsoclonus myoclonus syndrome, IgG4-related disease, Psoriasis,        Reactive arthritis, Rheumatoid arthritis, Juvenile idiopathic        arthritis, Sarcoidosis, Sjögren syndrome, Systemic lupus        erythematosus, Type I diabetes, Vitiligo, or Ulcerative colitis.    -   186. The method of paragraph 185, wherein the autoimmune disease        is multiple sclerosis or Crohn's disease.    -   187. The method of any one of paragraphs 175 to 186, wherein the        one or more immunosuppressive medications comprise a        glucocorticoid, cytostatic, antibody, drug acting on        immunophilins, interferon, opioid, TNF binding protein,        mycophenolate, small biological agent, small molecule, organic        compound, or any combination thereof.    -   188. The method of any one of paragraphs 175 to 187, wherein the        one or more immunosuppressive medications comprise a interferon        beta-1a, interferon beta-1b, glatiramer acetate, peginterferon        beta-1a, teriflunomide, fingolimod, dimethyl fumarate,        alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,        ocrelizumab, diroximel fumarate, siponimod or any combination        thereof.    -   189. The method of paragraph 188, wherein the one or more        immunosuppressive medications comprise natalizumab.    -   190. The method of any one of paragraphs 175 to 189, wherein the        one or more genetic variations comprise a point mutation,        polymorphism, single nucleotide polymorphisms (SNP), single        nucleotide variation (SNV), translocation, insertion, deletion,        amplification, inversion, interstitial deletion, copy number        variation (CNV), structural variation (SV), loss of        heterozygosity, or any combination thereof.    -   191. The method of any one of paragraphs 175 to 190, wherein the        one or more genetic variations result in a loss of function of        the corresponding gene.    -   192. The method of any one of paragraphs 175 to 191, wherein the        corresponding gene comprises a gene selected from the group        consisting of gene numbers (GNs) GN1-GN765.    -   193. The method of any one of paragraphs 175 to 191, wherein the        gene comprises a gene selected from the group consisting of gene        numbers (GNs) GN1-GN156 in Table 3.    -   194. The method of any one of paragraphs 175 to 191, wherein the        gene comprises a gene selected from the group consisting of gene        numbers (GNs) GN 2-4, 6, 8-13, 23-28, 31-39, 41-47, 51-57,        59-62, 64-67, 69, 72-75, 89, 92-95, 98-105, 107-120, 123-128,        130, 131, 133, 134, 136, 138-142, 145, 147, 148, 157-174,        176-179, 181-205, 207-239, 241, 243-307, 309-315, 317-353,        355-369, 371-435, 437, 439-482 and 484-490 in Table 6.    -   195. The method of any one of paragraphs 175 to 191, wherein the        gene comprises a gene selected from the group consisting of gene        numbers (GNs) GN491-GN492 in Table 29.    -   196. The method of any one of paragraphs 175 to 191, wherein the        gene comprises a gene selected from the group consisting of gene        numbers (GNs) GN493-GN762 in Table 31.    -   197. The method of any one of paragraphs 175 to 191, wherein the        gene comprises a gene selected from the group consisting of gene        numbers (GNs) GN763-GN765 in Table 48.    -   198. The method of any one of paragraphs 175 to 191, wherein the        corresponding gene comprises a gene selected from Tables 34-40,        and 42.    -   199. The method of any one of paragraphs 175 to 191, wherein the        gene comprises a gene selected from the group consisting of        PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE,        LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A,        PIK3CD, PNP, MCEE, DOCK2 and ALG12.    -   200. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        encoded by a sequence with at least 60%, at least 70%, at least        80%, at least 90%, at least 95%, or at least 99% sequence        identity to SEQ ID NOs 1-172, 2200-2203, or SRN1-SRN366, with        100% sequence identity to SEQ ID NOs 1000-1329, 3000-3274, or        with at least 80% and less than 100% sequence identity to        GN1-GN765, or complements thereof.    -   201. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations are encoded by a sequence with at        least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203,        or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs        3000-3274, or with at least 80% and less than 100% sequence        identity to GN491-GN765, or complements thereof.    -   202. The method of paragraph 200, wherein the one or more        genetic variations comprise a genetic variation encoded by a CNV        with at least 60%, at least 70%, at least 80%, at least 90%, at        least 95%, or at least 99% sequence identity to SEQ ID NOs        1-172, or complements thereof.    -   203. The method of paragraph 200, wherein the one or more        genetic variations comprise a genetic variation encoded by a CNV        with at least 60%, at least 70%, at least 80%, at least 90%, at        least 95%, or at least 99% sequence identity to SEQ ID NOs        2200-2203, or complements thereof.    -   204. The method of paragraph 200, wherein the one or more        genetic variations comprise a genetic variation encoded by a CNV        sub-region (SRN) with at least 60%, at least 70%, at least 80%,        at least 90%, at least 95%, or at least 99% sequence identity to        SRN1-SRN363, or complements thereof.    -   205. The method of paragraph 200, wherein the one or more        genetic variations comprise a genetic variation encoded by a CNV        sub-region (SRN) with at least 60%, at least 70%, at least 80%,        at least 90%, at least 95%, or at least 99% sequence identity to        SRN364-SRN366, or complements thereof.    -   206. The method of paragraph 200, wherein the one or more        genetic variations are encoded by a single nucleotide variation        (SNV) with a sequence of any one of SEQ ID NOs: 1000-1329, or        complements thereof.    -   207. The method of paragraph 200, wherein the one or more        genetic variations comprise a genetic variation encoded by a        single nucleotide variation (SNV) with a sequence of any one of        SEQ ID NOs: 3000-3274, or complements thereof.    -   208. The method of paragraph 200, wherein the one or more        genetic variations comprise a genetic variation encoded by a        sequence with at least 80% and less than 100% sequence identity        to GN1-GN490, or complements thereof.    -   209. The method of paragraph 200, wherein the one or more        genetic variations comprise a genetic variation encoded by a        sequence with at least 80% and less than 100% sequence identity        to GN491-GN765, or complements thereof.    -   210. The method of paragraph 200, wherein the one or more        genetic variations comprise a genetic variation encoded by a        single nucleotide variation (SNV) with a sequence of any one of        SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016,        1017, 1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037,        1040, 1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061,        1062, 1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075,        1076, 1077, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099,        1100, 1101, 1104, 1107, 1114, 1116, 1118, 1121, 1122, 1123,        1125, 1126, 1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136,        1137, 1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157,        1160, 1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175,        1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193,        1194, 1200, 1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221,        1222, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239,        1247, 1248, 1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259,        1260, 1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283,        1284, 1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304,        1311, 1327 or 1328, or complements thereof.    -   211. The method of paragraph 210, wherein the one or more        genetic variations comprise a genetic variation encoded by a        single nucleotide variation (SNV) with a sequence of any one of        SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056,        1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135,        1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184,        1193, 1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255,        1256, 1259, 1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287,        1289, 1299 or 1311, or complements thereof.    -   212. The method of paragraph 210, wherein the one or more        genetic variations comprise a genetic variation encoded by a        single nucleotide variation (SNV) with a sequence of any one of        SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017,        1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059,        1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076,        1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104,        1107, 1116, 1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133,        1136, 1137, 1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165,        1166, 1168, 1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180,        1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226,        1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250,        1251, 1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286,        1290, 1291, 1300, 1301, 1304, 1327 or 1328, or complements        thereof.    -   213. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr16:81942175 A>G,        chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T,        chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A,        chr3:39323163 A>C, chr4:151199080 G>A, chr1:42047208 C>G,        chr2:163124051 C>T, chr1:182554557 C>T, chr8:145154824 A>C,        chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G,        chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T,        chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T,        chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C,        chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T,        chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A,        chr19:7712287 G>C, chr10:90771767 G>A, chr3:121415370 T>C,        chr16:70503095 A>G, chr1:206945738 C>T, chr5:156593120 C>T,        chr4:27019452 C>T, chr1:155317682 C>T, chr17:77926526 C>T,        chr1:235840495 G>T, chr14:21993359 G>A, chr8:61757805 C>T,        chr15:91306241 G>A, chr16:50741791 C>T, chr22:23915583 T>C,        chr2:47205921 C>T, chr12:88900891 C>A, chr3:142281353 C>G,        chr11:108123551 C>T, chr1:207641950 C>T, chr6:143092151 T>C,        chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134 G>A,        chr8:100205255 G>A, chr21:16339852 T>C, and any combination        thereof, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   214. The method of paragraph 213, wherein the one or more        genetic variations comprise a genetic variation selected from        the group consisting of chr16:81942175 A>G, chr2:163136505 C>G,        chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T,        chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C,        chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,        chr1:182554557 C>T, and any combination thereof, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   215. The method of paragraph 213, wherein the one or more        genetic variations comprise a genetic variation selected from        the group consisting of chr8:145154824 A>C, chr20:62305450 C>T,        chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,        chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,        chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,        chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,        chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A,        chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C,        chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,        chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,        chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,        chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,        chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,        chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,        chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T,        chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A,        chr21:16339852 T>C, and any combination thereof, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   216. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr1:196759282, C>T,        chr4:126412634, C>G, chr10:75673748, A>C, chr6:30675830, T>A,        chr6:30680721, G>A, chr12:56385915, GGGA>G, chr18:57103126, G>A,        chr3:171321023, C>T, chr1:59131311, G>T, chr22:31008867, T>C,        chr2:74690378, C>T, chr17:7592168, C>G, chr2:74690039, G>A,        chr12:113448288, A>G, chr17:76130947, G>T, chr2:15674686, T>C,        chr2:15607842, T>C, chr14:94847262, T>A, chr4:126412154, G>A,        chr22:37271882, T>C, chr20:44640959, G>A, chr17:8138569, C>G,        chr12:113357237, G>C, chr12:113357209, G>A, chr11:60893235, C>T,        chr12:113357442, G>A, chr5:40964852, A>C, chr14:35497285, T>C,        chr19:55494157, G>A, and any combination thereof, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   217. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr11:72145307, C>G,        chr7:30491421, G>T, chr6:30673403, A>G, chr19:44153248, T>C,        chr17:43555253, A>G, chr2:188349523, A>G, chr1:57409459, C>A,        chr4:126241248, C>G, chr5:39311336, A>T, chr17:76129619, C>T,        chr4:110929301, T>C, chr3:11402163, G>A, chr16:67694044, C>T,        chr19:10395141, G>A, chr6:106740989, T>C, chr1:183532364, T>A,        chr22:35806756, G>A, chr4:110865044, G>C, chr4:110864533, C>T,        chr4:126238090, G>T, chr4:110932508, C>A, chr6:31605016, T>C,        chr7:92733766, C>A, chr18:29645930, A>T, and any combination        thereof, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   218. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr21:45708278, G>A,        chr11:108106443, T>A, chr1:57409459, C>A, chr1:196918605, A>G,        chr3:58191230, G>T, chr2:230579019, G>A, chr9:137779251, G>A,        chr1:27699670, AG>A, chr1:92946625, G>C, chr1:42047208, C>G,        chr2:163136505, C>G, chr22:23915583, T>C, chr22:23915745, G>A,        chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A,        chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A,        chr6:51798908, C>T, chr16:81942175, A>G, chr19:8564523, T>G,        chr14:94847262, T>A, chr19:7712287, G>C, chr6:32814942, C>T,        chr6:32816772, C>A and chr11:67818269, G>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   219. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr22:23915745, G>A,        chr6:30673359, T>G, chr19:7712287, G>C, chr9:137779251, G>A,        chr22:23915583, T>C, chr22:35806756, G>A and chr2:163136505,        C>G, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   220. In some embodiments, the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr19:8564523, T>G, chr11:108106443, T>A, chr6:32816772, C>A,        chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A,        chr2:230579019, G>A, chr14:94847262, T>A and chr4:151793903,        T>C, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   221. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr22:23915745, G>A,        chr6:30673359, T>G, chr19:7712287, G>C, chr19:8564523, T>G,        chr11:108106443, T>A, chr9:137779251, G>A, chr22:23915583, T>C,        chr22:35806756, G>A, chr2:163136505, C>G, chr6:32816772, C>A,        chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A,        chr2:230579019, G>A, chr14:94847262 and T>A, chr4:151793903,        T>C, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   222. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr1:160769595, AG>A,        chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,        chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,        chr1:57409459, C>A, chr3:58191230, G>T and chr16:81942175, A>G,        wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   223. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr19:8564523, T>G,        chr1:42047208, C>G and chr11:67818269, G>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   224. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr1:160769595, AG>A,        chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,        chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,        chr19:8564523, T>G, chr1:57409459, C>A, chr3:58191230, G>T,        chr16:81942175, A>G, chr1:42047208, C>G and chr11:67818269, G>A,        wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   225. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr6:51798908, C>T,        chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,        chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,        chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,        chr9:137779251, G>A, chr19:7712287, G>C and chr16:81942175, A>G,        wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   226. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr6:32816772, C>A,        chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C,        chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A        and chr14:94847262, T>A, wherein chromosome positions of the one        or more genetic variations are defined with respect to UCSC        hg19.    -   227. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr6:51798908, C>T,        chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,        chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,        chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,        chr9:137779251, G>A, chr19:7712287, G>C, chr16:81942175, A>G,        chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C,        chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,        chr1:27699670, AG>A and chr14:94847262, T>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   228. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr1:160769595, AG>A,        chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,        chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,        chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,        chr11:67818269, G>A and chr16:81942175, A>G, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   229. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr19:48643270, C>T,        chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,        chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,        chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and        chr14:94847262, T>A, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   230. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of chr1:160769595, AG>A,        chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,        chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,        chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,        chr11:67818269, G>A, chr16:81942175, A>G, chr19:48643270, C>T,        chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,        chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,        chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and        chr14:94847262, T>A, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   231. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations do not comprise a genetic        variation of chr2:163136505, C>G, wherein chromosome positions        of the one or more genetic variations are defined with respect        to UCSC hg19.    -   232. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations do not comprise a genetic        variation of chr22:23915745, G>A, wherein chromosome positions        of the one or more genetic variations are defined with respect        to UCSC hg19.    -   233. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations do not comprise a genetic        variation of chr16:81942175, A>G, wherein chromosome positions        of the one or more genetic variations are defined with respect        to UCSC hg19.    -   234. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations do not comprise a genetic        variation of chr19:7712287, G>C, wherein chromosome positions of        the one or more genetic variations are defined with respect to        UCSC hg19.    -   235. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations do not comprise a genetic        variation of chr11:67818269, G>A, wherein chromosome positions        of the one or more genetic variations are defined with respect        to UCSC hg19.    -   236. The method of any one of paragraphs 175 to 191, wherein the        one or more genetic variations do not comprise a genetic        variation of chr2:163136505, C>G; chr22:23915745, G>A;        chr16:81942175, A>G; chr19:7712287, G>C; and chr11:67818269,        G>A, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   237. The method of any one of paragraphs 200-215, wherein the        SNV is a heterozygous SNV.    -   238. The method of any one of paragraphs 200-215, wherein the        SNV is a homozygous SNV.    -   239. The method of any one of paragraphs 200-237, wherein the        one or more genetic variations comprise a pair of single        nucleotide variations (SNVs), wherein the pair of SNVs are        encoded by any one of SEQ ID NO pairs: 1003 and 1004, 1003 and        1005, 1006 and 1007, 1024 and 1025, 1030 and 1031, 1047 and        1048, 1049 and 1050, 1063 and 1064, 1063 and 1065, 1063 and        1066, 1075 and 1076, 1091 and 1093, 1091 and 1096, 1093 and        1095, 1094 and 1097, 1098 and 1099, 1098 and 1100, 1099 and        1100, 1102 and 1103, 1104 and 1106, 1104 and 1107, 1104 and        1108, 1104 and 1109, 1104 and 1110, 1104 and 1111, 1104 and        1112, 1110 and 1111, 1112 and 1113, 1119 and 1120, 1124 and        1125, 1124 and 1126, 1125 and 1126, 1140 and 1141, 1142 and        1144, 1146 and 1151, 1147 and 1148, 1147 and 1149, 1153 and        1146, 1153 and 1147, 1155 and 1156, 1160 and 1161, 1165 and        1166, 1186 and 1187, 1188 and 1193, 1189 and 1193, 1191 and        1192, 1191 and 1193, 1191 and 1195, 1192 and 1193, 1192 and        1195, 1196 and 1197, 1206 and 1207, 1210 and 1218, 1211 and        1213, 1212 and 1213, 1213 and 1215, 1213 and 1216, 1213 and        1217, 1233 and 1238, 1242 and 1243, 1245 and 1246, 1263 and        1260, 1269 and 1279, 1270 and 1279, 1270 and 1282, 1271 and        1279, 1274 and 1279, 1278 and 1279, 1278 and 1281, 1279 and        1280, 1279 and 1281, 1279 and 1282, 1292 and 1293, 1296 and        1297, 1305 and 1314, 1306 and 1310, 1313 and 1321 or 1315 and        1322, or complements thereof.    -   240. The method of any one of paragraphs 200-239, wherein the        one or more genetic variations comprise a genetic variation        encoded by a CNV with at least 60%, at least 70%, at least 80%,        at least 90%, at least 95%, or at least 99% sequence identity to        any one of SEQ ID NOs 157, 2, 140, 65, 26, 14 or 45, or        complements thereof.    -   241. The method of paragraph 240, wherein the one or more        genetic variations comprise a genetic variation encoded by a CNV        with at least 60%, at least 70%, at least 80%, at least 90%, at        least 95%, or at least 99% sequence identity to any one of SEQ        ID NOs 2, 140, 65, 26, 14 or 45, or complements thereof.    -   242. The method of paragraph 240, wherein the one or more        genetic variations comprise a genetic variation encoded by a CNV        with at least 60%, at least 70%, at least 80%, at least 90%, at        least 95%, or at least 99% sequence identity to SEQ ID NO 157,        or a complement thereof.    -   243. The method of any one of paragraphs 200-242, wherein the        one or more genetic variations comprise a CNV-SNV pair        comprising a CNV and a single nucleotide variation (SNV),        wherein the SNV of the CNV-SNV pair is encoded by any one of SEQ        ID NOs 1301, 1173, 1107, 1104, 1199, 1225, 1086 or 1223, or        complements thereof.    -   244. The method of any one of paragraphs 200-243, wherein the        one or more genetic variations comprise a genetic variation        selected from the group consisting of one or more of the        following: chr8:145154222 G>A, chr2:163136505 C>G,        chr16:81942175 A>G, and chr8:61654298 T>A.    -   245. The method of any one of paragraphs 200-244, wherein the        one or more genetic variations disrupt or modulate one or more        of the following genes: PLCG2, POLE, LRBA, EPG5 and SHARPIN.    -   246. The method of any one of paragraphs 200-244, wherein the        one or more genetic variations disrupt or modulate one or more        of the following genes: PLCG2, CHD7, IFIH1, AP3B1, EPG5, PIK3CD,        LRBA and SHARPIN.    -   247. The method of any one of paragraphs 175-246, wherein the        gene encodes a transcript with a sequence that has at least 60%,        at least 70%, at least 80%, at least 90%, at least 95%, or at        least 99% sequence identity to any one of SEQ ID NOs 173-455 or        1500-2177, or complements thereof.    -   248. The method of paragraph 247, wherein the gene encodes a        transcript with a sequence that has at least 60%, at least 70%,        at least 80%, at least 90%, at least 95%, or at least 99%        sequence identity to any one of SEQ ID NOs 173-455, or        complements thereof.    -   249. The method of paragraph 247, wherein the gene encodes a        transcript with a sequence that has at least 60%, at least 70%,        at least 80%, at least 90%, at least 95%, or at least 99%        sequence identity to any one of SEQ ID NOs 1500-2177, or        complements thereof.    -   250. The method of any one of paragraphs 200-249, wherein the        one or more genetic variations comprise 2 or 3 or 4 or 5 or more        genetic variations.    -   251. The method of paragraph 250, wherein the one or more        genetic variations comprise 10 or more genetic variations.    -   252. The method of paragraph 250, wherein the one or more        genetic variations comprise 20 or more genetic variations.    -   253. The method of paragraph 250, wherein the one or more        genetic variations comprise 50 or more genetic variations.    -   254. The method of any one of paragraphs 175, 176, and 181 to        253, wherein the analyzing comprises microarray analysis, PCR,        sequencing, nucleic acid hybridization, or any combination        thereof.    -   255. The method of any one of paragraphs 177 to 179 and 182 to        253, wherein the genetic test result comprises a genetic test        result from a microarray analysis, PCR, sequencing, nucleic acid        hybridization, or any combination thereof.    -   256. The method of any one of paragraphs 180 and 182 to 253,        wherein the detecting comprises a microarray analysis, PCR,        sequencing, nucleic acid hybridization, or any combination        thereof.    -   257. The method of any one of paragraphs 254 to 256, wherein the        microarray analysis selected from the group consisting of a        Comparative Genomic Hybridization (CGH) array analysis and an        SNP array analysis.    -   258. The method of any one of paragraphs 254 to 256, wherein the        sequencing is selected from the group consisting of Massively        Parallel Signature Sequencing (MPSS), polony sequencing, 454        pyrosequencing, Illumina sequencing, Illumina (Solexa)        sequencing using 10× Genomics library preparation, SOLiD        sequencing, ion semiconductor sequencing, DNA nanoball        sequencing, heliscope single molecule sequencing, single        molecule real time (SMRT) sequencing, RNAP sequencing, Nanopore        DNA sequencing, sequencing by hybridization, and microfluidic        Sanger sequencing.    -   259. The method of any one of paragraphs 254, 257, and 258,        wherein the analyzing comprises analyzing a whole genome or a        whole exome of the subject.    -   260. The method of any one of paragraphs 254, 257, and 258,        wherein the analyzing comprises analyzing nucleic acid        information that has already been obtained for a whole genome or        a whole exome of the subject.    -   261. The method of paragraph 260, wherein the nucleic acid        information is obtained from an in silico analysis.    -   262. The method of any one of paragraphs 255, 257, and 258,        wherein the analyzing comprises analyzing a whole genome or a        whole exome of the subject.    -   263. The method of any one of paragraphs 255, 257, and 258,        wherein the analyzing comprises analyzing nucleic acid        information that has already been obtained for a whole genome or        a whole exome of the subject.    -   264. The method of paragraph 263, wherein the nucleic acid        information is obtained from an in silico analysis.    -   265. The method of any one of paragraphs 256 to 258, wherein the        detecting comprises analyzing a whole genome or a whole exome of        the subject.    -   266. The method of any one of paragraphs 256 to 258, wherein the        detecting comprises analyzing nucleic acid information that has        already been obtained for a whole genome or a whole exome of the        subject.    -   267. The method of paragraph 266, wherein the nucleic acid        information is obtained from an in silico analysis.    -   268. The method of any one of paragraphs 175 to 267, wherein the        subject is a human subject.    -   269. The method of any one of paragraphs 175 to 268, wherein the        polynucleic acid sample comprises a polynucleic acid from blood,        saliva, urine, serum, tears, skin, tissue, or hair of the        subject.    -   270. The method of any one of paragraphs 175 to 269, wherein the        method further comprises analyzing for a presence of JCV in a        biological sample from the subject.    -   271. The method of paragraph 270, wherein the analyzing for a        presence of JCV comprises contacting a JCV detection reagent to        the biological sample.    -   272. The method of paragraph 271, wherein the JCV detection        reagent is selected from the group consisting of an anti-JCV        antibody, a JCV specific primer, and combinations thereof.    -   273. A kit, comprising reagents for assaying a polynucleic acid        sample from a subject in need thereof for the presence of one or        more genetic variations that disrupt or modulate a gene of        GN1-GN490.    -   274. The kit of paragraph 273, wherein the reagents comprise at        least one contiguous oligonucleotide that hybridizes to a        fragment of the polynucleic acid sample.    -   275. The kit of paragraph 273 or 274, wherein the reagents        comprise at least one pair of oligonucleotides that hybridize to        opposite strands of a fragment of the polynucleic acid sample.    -   276. The kit of any one of paragraphs 273 to 275, wherein the        kit further comprises one or more immunosuppressive medications.    -   277. The kit of paragraph 276, wherein the one or more        immunosuppressive medications comprise a glucocorticoid,        cytostatic, antibody, drug acting on immunophilins, interferon,        opioid, TNF binding protein, mycophenolate, small biological        agent, or any combination thereof.    -   278. The kit of paragraph 276 or 277, wherein the one or more        immunosuppressive medications comprise a interferon beta-1a,        interferon beta-1b, glatiramer acetate, peginterferon beta-1a,        teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab,        mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab,        diroximel fumarate or siponimod or any combination thereof.    -   279. The kit of paragraph 278, wherein the one or more        immunosuppressive medications comprise natalizumab.    -   280. The kit of any one of paragraphs 273 to 279, wherein the        kit further comprises a JCV detection reagent.    -   281. The method of paragraph 280, wherein the JCV detection        reagent is selected from the group consisting of an anti-JCV        antibody, a JCV specific primer, and combinations thereof.    -   282. The kit of any one of paragraphs 273 to 281, wherein the        kit further comprises a set of instructions for administration        of the one or more immunosuppressive medications.    -   283. The kit of any one of paragraphs 273 to 282, wherein the        one or more genetic variations comprise a point mutation,        polymorphism, single nucleotide polymorphisms (SNP), single        nucleotide variation (SNV), translocation, insertion, deletion,        amplification, inversion, interstitial deletion, copy number        variation (CNV), structural variation (SV), loss of        heterozygosity, or any combination thereof.    -   284. The kit of any one of paragraphs 273 to 283, wherein the        one or more genetic variations result in a loss of function of        the corresponding gene.    -   285. The kit of any one of paragraphs 273 to 284, wherein the        one or more genetic variations comprise 5 or more genetic        variations.    -   286. The kit of paragraph 285, wherein the one or more genetic        variations comprise 10 or more genetic variations.    -   287. The kit of paragraph 285, wherein the one or more genetic        variations comprise 20 or more genetic variations.    -   288. The kit of paragraph 285, wherein the one or more genetic        variations comprise 50 or more genetic variations.    -   289. The kit of any one of paragraphs 273 to 288, wherein the        subject is a human subject.    -   290. The kit of any one of paragraphs 273 to 289, wherein the        polynucleic acid sample comprises a polynucleic acid from blood,        saliva, urine, serum, tears, skin, tissue, or hair of the        subject.    -   291. A panel of polynucleic acids for detecting one or more        genetic variations that disrupt or modulate a gene of GN1-GN765,        wherein each polynucleic acid of the panel comprises a sequence        complementary to a sequence of one or more genetic variation or        complements thereof that disrupts or modulates a gene selected        from the group consisting of GN1-GN765.    -   292. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a sequence with at least        60%, at least 70%, at least 80%, at least 90%, at least 95%, or        at least 99% sequence identity to SEQ ID NOs 1-172, 2200-2203,        or SRN1-SRN366, with 100% sequence identity to SEQ ID NOs        1000-1329, 3000-3274, or with at least 80% and less than 100%        sequence identity to GN1-GN765, or complements thereof.    -   293. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations are        encoded by a sequence with at least 60%, at least 70%, at least        80%, at least 90%, at least 95%, or at least 99% sequence        identity to SEQ ID NOs 2200-2203 or SRN364-SRN366, with 100%        sequence identity to SEQ ID NOs 3000-3274, or with at least 80%        and less than 100% sequence identity to GN491-GN765, or        complements thereof.    -   294. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a CNV with at least 60%,        at least 70%, at least 80%, at least 90%, at least 95%, or at        least 99% sequence identity to SEQ ID NOs 1-172, or complements        thereof.    -   295. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a CNV with at least 60%,        at least 70%, at least 80%, at least 90%, at least 95%, or at        least 99% sequence identity to SEQ ID NOs 2200-2203, or        complements thereof.    -   296. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a CNV sub-region (SRN)        with at least 60%, at least 70%, at least 80%, at least 90%, at        least 95%, or at least 99% sequence identity to SRN1-SRN363, or        complements thereof.    -   297. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a CNV sub-region (SRN)        with at least 60%, at least 70%, at least 80%, at least 90%, at        least 95%, or at least 99% sequence identity to SRN364-SRN366,        or complements thereof.    -   298. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a single nucleotide        variation (SNV) with a sequence of any one of SEQ ID NOs:        1000-1329, or complements thereof.    -   299. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a single nucleotide        variation (SNV) with a sequence of any one of SEQ ID NOs:        3000-3274, or complements thereof.    -   300. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a sequence with at least        80% and less than 100% sequence identity to GN1-GN490, or        complements thereof.    -   301. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a sequence with at least        80% and less than 100% sequence identity to GN491-GN765, or        complements thereof.    -   302. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a single nucleotide        variation (SNV) with a sequence of any one of SEQ ID NO: 1000,        1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016, 1017, 1019,        1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037, 1040, 1041,        1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062, 1063,        1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076, 1077,        1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1101,        1104, 1107, 1114, 1116, 1118, 1121, 1122, 1123, 1125, 1126,        1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136, 1137, 1138,        1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157, 1160, 1161,        1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176, 1177,        1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200,        1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226,        1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239, 1247, 1248,        1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259, 1260, 1261,        1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283, 1284, 1286,        1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311, 1327 or        1328, or complements thereof.    -   303. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a single nucleotide        variation (SNV) with a sequence of any one of SEQ ID NO: 1011,        1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056, 1069, 1073,        1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135, 1142, 1146,        1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184, 1193, 1194,        1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255, 1256, 1259,        1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287, 1289, 1299 or        1311, or complements thereof.    -   304. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a single nucleotide        variation (SNV) with a sequence of any one of SEQ ID NO: 1000,        1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017, 1019, 1033,        1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059, 1061, 1062,        1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076, 1078, 1080,        1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104, 1107, 1116,        1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133, 1136, 1137,        1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165, 1166, 1168,        1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182,        1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226, 1227, 1228,        1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250, 1251, 1252,        1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286, 1290, 1291,        1300, 1301, 1304, 1327 or 1328, or complements thereof.    -   305. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A,        chr22:23917192 G>T, chr20:3846397 C>T, chr8:145154222, G>A        chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A,        chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T,        chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A,        chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T,        chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT,        chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C,        chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G,        chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G,        chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A,        chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T,        chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T,        chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A,        chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T,        chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A,        chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T,        chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T,        chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any        combination thereof, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   306. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A,        chr22:23917192 G>305, chr20:3846397 C>T, chr8:145154222, G>A        chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A,        chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T, and        any combination thereof, wherein chromosome positions of the one        or more genetic variations are defined with respect to UCSC        hg19.    -   307. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A,        chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T,        chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT,        chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C,        chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G,        chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G,        chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A,        chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T,        chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T,        chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A,        chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T,        chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A,        chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T,        chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T,        chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any        combination thereof, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   308. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr1:196759282, C>T, chr4:126412634, C>G, chr10:75673748,        A>C, chr6:30675830, T>A, chr6:30680721, G>A, chr12:56385915,        GGGA>G, chr18:57103126, G>A, chr3:171321023, C>T, chr1:59131311,        G>T, chr22:31008867, T>C, chr2:74690378, C>T, chr17:7592168,        C>G, chr2:74690039, G>A, chr12:113448288, A>G, chr17:76130947,        G>T, chr2:15674686, T>C, chr2:15607842, T>C, chr14:94847262,        T>A, chr4:126412154, G>A, chr22:37271882, T>C, chr20:44640959,        G>A, chr17:8138569, C>G, chr12:113357237, G>C, chr12:113357209,        G>A, chr11:60893235, C>T, chr12:113357442, G>A, chr5:40964852,        A>C, chr14:35497285, T>C, chr19:55494157, G>A, and any        combination thereof, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   309. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr11:72145307, C>G, chr7:30491421, G>T, chr6:30673403, A>G,        chr19:44153248, T>C, chr17:43555253, A>G, chr2:188349523, A>G,        chr1:57409459, C>A, chr4:126241248, C>G, chr5:39311336, A>T,        chr17:76129619, C>T, chr4:110929301, T>C, chr3:11402163, G>A,        chr16:67694044, C>T, chr19:10395141, G>A, chr6:106740989, T>C,        chr1:183532364, T>A, chr22:35806756, G>A, chr4:110865044, G>C,        chr4:110864533, C>T, chr4:126238090, G>T, chr4:110932508, C>A,        chr6:31605016, T>C, chr7:92733766, C>A, chr18:29645930, A>T, and        any combination thereof, wherein chromosome positions of the one        or more genetic variations are defined with respect to UCSC        hg19.    -   310. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr21:45708278, G>A, chr11:108106443, T>A, chr1:57409459,        C>A, chr1:196918605, A>G, chr3:58191230, G>T, chr2:230579019,        G>A, chr9:137779251, G>A, chr1:27699670, AG>A, chr1:92946625,        G>C, chr1:42047208, C>G, chr2:163136505, C>G, chr22:23915583,        T>C, chr22:23915745, G>A, chr19:48643270, C>T, chr4:151793903,        T>C, chr1:160769595, AG>A, chr22:35806756, G>A, chr6:30673359,        T>G, chr6:3015818, G>A, chr6:51798908, C>T, chr16:81942175, A>G,        chr19:8564523, T>G, chr14:94847262, T>A, chr19:7712287, G>C,        chr6:32814942, C>T, chr6:32816772, C>A and chr11:67818269, G>A,        wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   311. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C,        chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A        and chr2:163136505, C>G. In some embodiments, the one or more        genetic variations comprise a genetic variation selected from        the group consisting of chr19:8564523, T>G, chr11:108106443,        T>A, chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175,        A>G, chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262,        T>A and chr4:151793903, T>C, wherein chromosome positions of the        one or more genetic variations are defined with respect to UCSC        hg19.    -   312. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C,        chr19:8564523, T>G, chr11:108106443, T>A, chr9:137779251, G>A,        chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,        chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G,        chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262 and        T>A, chr4:151793903, T>C, wherein chromosome positions of the        one or more genetic variations are defined with respect to UCSC        hg19.    -   313. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908,        C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605,        A>G, chr6:3015818, G>A, chr1:57409459, C>A, chr3:58191230, G>T        and chr16:81942175, A>G, wherein chromosome positions of the one        or more genetic variations are defined with respect to UCSC        hg19.    -   314. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr19:8564523, T>G, chr1:42047208, C>G and chr11:67818269,        G>A, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   315. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908,        C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605,        A>G, chr6:3015818, G>A, chr19:8564523, T>G, chr1:57409459, C>A,        chr3:58191230, G>T, chr16:81942175, A>G, chr1:42047208, C>G and        chr11:67818269, G>A, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   316. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605,        A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A,        chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G,        chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C and        chr16:81942175, A>G, wherein chromosome positions of the one or        more genetic variations are defined with respect to UCSC hg19.    -   317. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C,        chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,        chr1:27699670, AG>A and chr14:94847262, T>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   318. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605,        A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A,        chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G,        chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C,        chr16:81942175, A>G, chr6:32816772, C>A, chr6:32814942, C>T,        chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A,        chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262,        T>A, wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   319. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A,        chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A,        chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A,        chr19:7712287, G>C, chr11:67818269, G>A and chr16:81942175, A>G,        wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19.    -   320. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C,        chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A,        chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A,        chr4:151793903, T>C and chr14:94847262, T>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   321. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A,        chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A,        chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A,        chr19:7712287, G>C, chr11:67818269, G>A, chr16:81942175, A>G,        chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C,        chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A,        chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A,        chr4:151793903, T>C and chr14:94847262, T>A, wherein chromosome        positions of the one or more genetic variations are defined with        respect to UCSC hg19.    -   322. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations do not        comprise a genetic variation of chr2:163136505, C>G, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   323. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations do not        comprise a genetic variation of chr22:23915745, G>A, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   324. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations do not        comprise a genetic variation of chr16:81942175, A>G, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   325. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations do not        comprise a genetic variation of chr19:7712287, G>C, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   326. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations do not        comprise a genetic variation of chr11:67818269, G>A, wherein        chromosome positions of the one or more genetic variations are        defined with respect to UCSC hg19.    -   327. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations do not        comprise a genetic variation of chr2:163136505, C>G;        chr22:23915745, G>A; chr16:81942175, A>G; chr19:7712287, G>C;        and chr11:67818269, G>A, wherein chromosome positions of the one        or more genetic variations are defined with respect to UCSC        hg19.    -   328. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the SNV is a heterozygous SNV.    -   329. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the SNV is a homozygous SNV.    -   330. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a pair of single nucleotide variations (SNVs), wherein        the pair of SNVs are encoded by any one of SEQ ID NO pairs: 1003        and 1004, 1003 and 1005, 1006 and 1007, 1024 and 1025, 1030 and        1031, 1047 and 1048, 1049 and 1050, 1063 and 1064, 1063 and        1065, 1063 and 1066, 1075 and 1076, 1091 and 1093, 1091 and        1096, 1093 and 1095, 1094 and 1097, 1098 and 1099, 1098 and        1100, 1099 and 1100, 1102 and 1103, 1104 and 1106, 1104 and        1107, 1104 and 1108, 1104 and 1109, 1104 and 1110, 1104 and        1111, 1104 and 1112, 1110 and 1111, 1112 and 1113, 1119 and        1120, 1124 and 1125, 1124 and 1126, 1125 and 1126, 1140 and        1141, 1142 and 1144, 1146 and 1151, 1147 and 1148, 1147 and        1149, 1153 and 1146, 1153 and 1147, 1155 and 1156, 1160 and        1161, 1165 and 1166, 1186 and 1187, 1188 and 1193, 1189 and        1193, 1191 and 1192, 1191 and 1193, 1191 and 1195, 1192 and        1193, 1192 and 1195, 1196 and 1197, 1206 and 1207, 1210 and        1218, 1211 and 1213, 1212 and 1213, 1213 and 1215, 1213 and        1216, 1213 and 1217, 1233 and 1238, 1242 and 1243, 1245 and        1246, 1263 and 1260, 1269 and 1279, 1270 and 1279, 1270 and        1282, 1271 and 1279, 1274 and 1279, 1278 and 1279, 1278 and        1281, 1279 and 1280, 1279 and 1281, 1279 and 1282, 1292 and        1293, 1296 and 1297, 1305 and 1314, 1306 and 1310, 1313 and 1321        or 1315 and 1322, or complements thereof.    -   331. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a CNV with at least 60%,        at least 70%, at least 80%, at least 90%, at least 95%, or at        least 99% sequence identity to any one of SEQ ID NOs 157, 2,        140, 65, 26, 14 or 45, or complements thereof.    -   332. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a CNV with at least 60%,        at least 70%, at least 80%, at least 90%, at least 95%, or at        least 99% sequence identity to any one of SEQ ID NOs 2, 140, 65,        26, 14 or 45, or complements thereof.    -   333. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation encoded by a CNV with at least 60%,        at least 70%, at least 80%, at least 90%, at least 95%, or at        least 99% sequence identity to SEQ ID NO 157, or a complement        thereof.    -   334. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a CNV and a single nucleotide variations (SNV), wherein        SNVs is encoded by any one of SEQ ID NOs 1301, 1173, 1107, 1104,        1199, 1225, 1086 or 1223, or complements thereof.    -   335. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise a genetic variation selected from the group consisting        of one or more of the following: chr8:145154222 G>A,        chr2:163136505 C>G, chr16:81942175 A>G, and chr8:61654298 T>A,        wherein chromosome positions of the one or more genetic        variations are defined with respect to UCSC hg19. 336. The kit        of any one of paragraphs 273-290 or the panel of paragraph 291,        wherein the one or more genetic variations disrupt or modulate        one or more of the following genes: PLCG2, POLE, LRBA, EPG5 and        SHARPIN.    -   337. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        disrupt or modulate one or more of the following genes: PLCG2,        CHD7, IFIH1, AP3BI, EPG5, PIK3CD, LRBA and SHARPIN.    -   338. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the gene encodes a transcript with a        sequence that has at least 60%, at least 70%, at least 80%, at        least 90%, at least 95%, or at least 99% sequence identity to        any one of SEQ ID NOs 173455, 1500-2177, 2204-2215, 2300-2893,        or complements thereof.    -   339. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the gene encodes a transcript with a        sequence that has at least 60%, at least 70%, at least 80%, at        least 90%, at least 95%, or at least 99% sequence identity to        any one of SEQ ID NOs 173455, or complements thereof.    -   340. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the gene encodes a transcript with a        sequence that has at least 60%, at least 70%, at least 80%, at        least 90%, at least 95%, or at least 99% sequence identity to        any one of SEQ ID NOs 1500-2177, or complements thereof.    -   341. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the gene encodes a transcript with a        sequence that has at least 60%, at least 70%, at least 80%, at        least 90%, at least 95%, or at least 99% sequence identity to        any one of SEQ ID NOs 2204-2215, or complements thereof.    -   342. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the gene encodes a transcript with a        sequence that has at least 60%, at least 70%, at least 80%, at        least 90%, at least 95%, or at least 99% sequence identity to        any one of SEQ ID NOs 2300-2893, or complements thereof.    -   343. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the one or more genetic variations        comprise at least 5, at least 10, at least 20, or at least 50        genetic variations.    -   344. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein panel of polynucleic acids comprises at        least 5, at least 10, at least 20, or at least 50 polynucleic        acids.    -   345. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the gene comprises a gene selected from        the group consisting of gene numbers (GNs) GN1-GN156 in Table 3.    -   346. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the gene comprises a gene selected from        the group consisting of gene numbers (GNs) GN157-GN490 in Table        6.    -   347. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the corresponding gene comprises a gene        selected from the group consisting of gene numbers (GNs)        GN491-GN492 in Table 29.    -   348. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the corresponding gene comprises a gene        selected from the group consisting of gene numbers (GNs)        GN493-GN762 in Table 31.    -   349. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the corresponding gene comprises a gene        selected from the group consisting of gene numbers (GNs)        GN763-GN765 in Table 48.    -   350. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the corresponding gene comprises a gene        selected from Tables 34-40, and 42.    -   351. The kit of any one of paragraphs 273-290 or the panel of        paragraph 291, wherein the gene comprises a gene selected from        the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN,        PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST,        HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2 and ALG12.    -   352. A method to predict an adverse responsiveness of a subject        to a therapy, the method comprising        -   (a) detecting one or more genetic variations that disrupt or            modulate a gene of GN1-GN765 in a polynucleic acid sample            from the subject; and        -   (b) using that detection as a biomarker for predicting a            response of the subject to the therapy to be adverse,            wherein the therapy is an immunosuppressive therapy            comprising one or more immunosuppressive medications.    -   353. A method of screening for a PML biomarker comprising        -   (a) obtaining biological samples from subjects with PML;        -   (b) screening the biological samples to obtain nucleic acid            information;        -   (c) detecting one or more genetic variations that disrupt or            modulate a gene of GN1-GN765 in a polynucleic acid sample            from a subject suspected of having PML; and        -   (d) using that detection as a biomarker for predicting a            response of the subject to the therapy to be adverse,            wherein the therapy is an immunosuppressive therapy            comprising one or more immunosuppressive medications.    -   354. A method of screening for a PML biomarker comprising        -   (a) obtaining biological samples from subjects with PML;        -   (b) screening the biological samples to obtain nucleic acid            information;        -   (c) confirming each biological sample is not a duplicate of            any other biological sample based on the nucleic acid            information;        -   (d) detecting one or more genetic variations that disrupt or            modulate a gene of GN1-GN765 in a polynucleic acid sample            from a subject suspected of having PML; and        -   (e) using that detection as a biomarker for predicting a            response of the subject to the therapy to be adverse,            wherein the therapy is an immunosuppressive therapy            comprising one or more immunosuppressive medications.    -   355. A method of screening for a PML biomarker comprising        -   (a) obtaining biological samples from subjects with PML;        -   (b) screening the biological samples to obtain nucleic acid            information;        -   (c) determining a sex genotype for each biological sample            based on the nucleic acid information;        -   (d) confirming the sex genotype of each sample is the same            as a sex phenotype of the subject from the subjects with            PML;        -   (e) detecting one or more genetic variations that disrupt or            modulate a gene of GN1-GN765 in a polynucleic acid sample            from a subject suspected of having PML; and        -   (f) using that detection as a biomarker for predicting a            response of the subject to the therapy to be adverse,            wherein the therapy is an immunosuppressive therapy            comprising one or more immunosuppressive medications.    -   356. A method of treating a condition in a subject in need of        immunosuppressive therapy, comprising: administering a        therapeutically effective amount of one or more        immunosuppressive medications to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), and wherein the subject's decreased        risk is due to the absence of one or more genetic variations        that disrupt or modulate a gene, wherein a subject with the        disrupted or modulated gene has increased risk of progressive        multifocal leukoencephalopathy (PML) due to an infection of the        brain by John Cunningham virus (JCV).    -   357. A method of treating a condition in a subject in need of        natalizumab therapy, comprising: administering a therapeutically        effective amount of natalizumab to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), wherein the subject's decreased        risk is associated with an absence of one or more genetic        variations in the subject, wherein the subject has been tested        for a presence of the one or more genetic variations with a        genetic assay and has been identified as not having the one or        more genetic variations, wherein the one or more genetic        variations have an odds ratio (OR) of 3 or more, and wherein the        OR is: [DD/DN]/[ND/NN], wherein: DD is the number of subjects in        a diseased cohort of subjects with the one or more genetic        variations; DN is the number of subjects in the diseased cohort        without the one or more genetic variations; ND is the number of        subjects in a non-diseased cohort of subjects with the one or        more genetic variations; and NN is the number of subjects in the        non-diseased cohort without the one or more genetic variations,        wherein the diseased cohort of subjects have PML, and wherein        the non-diseased cohort of subjects do not have PML.    -   358. The method of paragraph 357, wherein the one or more        genetic variations have an OR of at least 4, 5, 6, 7, 8, 9, or        10.    -   359. The method of paragraph 357, wherein the one or more        genetic variations occur in one or more immune function-related        genes.    -   360. A method of treating a condition in a subject in need of        immunosuppressive therapy, comprising: administering a        therapeutically effective amount of one or more        immunosuppressive medications to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), and wherein the subject's decreased        risk is due to the absence of one or more genetic variations        that disrupt or modulates a corresponding gene according to        Tables 3, 6, 29, 31 and 48.    -   361. The method of any one of paragraphs 352-358, wherein the        one or more immunosuppressive medications comprise a        glucocorticoid, cytostatic, antibody, drug acting on        immunophilins, interferon, opioid, TNF binding protein,        mycophenolate, small biological agent, small molecule, organic        compound, or any combination thereof.    -   362. The method of any one of paragraphs 352-361, wherein the        one or more immunosuppressive medications comprise abatacept,        adalimumab, alefacept, alemtuzumab, anakinra, azathioprine,        belimumab, bendamustine, bevacizumab, bortezomib, brentuximab        vedotin, capecitabine, carboplatin, cetuximab, chlorambucil,        cladribine, cyclophosphamide, cyclosporine, daclizumab,        doxorubicin, diroximel fumarate, efalizumab, etanercept,        etoposide, fludarabine, gemcitabine, ibritumomab tiuxetan,        imatinib, infliximab, lenalidomide, methotrexate, mycophenolate        mofetil, natalizumab, oxaliplatin, rituximab, tocilizumab,        tofacitinib, ustekinumab, vedolizumab, vincristine, belatacept,        cytotoxic chemotherapy, corticosteroids, antithymocyte Ig,        basiliximab, muromonab-CD3, mycophenolic acid,        prednisone/prednisolone, sirolimus, tacrolimus, dimethyl        fumarate, fingolimod, ruxolitinib, interferon beta-1a,        interferon beta-1b, glatiramer acetate, peginterferon beta-1a,        teriflunomide, mitoxantrone, ocrelizumab, asparaginase,        bleomycin, busulfan, carmustine, certolizumab, ibrutinib,        idarubicin, idelalisib, hydrocortisone, ifosfamide, levamisole,        mercaptopurine, mizoribine, obinutuzumab, ofatumumab,        tegafur/gimeracil/oteracil, thiotepa, vinblastine, vincristine,        aldesleukin, azacitidine, atezolizumab, blinatumomab,        carfilzomib, cisplatin, cytarabine, daratumumab, dasatinib,        denosumab, dexamethasone, epirubicin, everolimus, fluorouracil,        golimumab, hydroxychloroquine sulfate, hydroxyurea, interferon        alfa-2, interferon gamma-1, ipilimumab, ixazomib, lapatinib,        leflunomide, melphalan, methylprednisone, nivolumab,        osimertinib, paclitaxel, pazopanib, pembrolizumab, pemetrexed,        pentostatin, pomalidomide, ponatinib, sorafenib, sunitinib,        temozolomide, thalidomide, venetoclax, vorinostat,        acalabrutinib, agatolimod sodium, alisertib, alvespimycin        hydrochloride, alvocidib, aminocamptothecin, andecaliximab,        anifrolumab, apatinib, apelisib, atacicept, avelumab, bafetinib,        baminercept, baricitinib, becatecarin, begelomab, bemcentinib,        betalutin with lilotomab, bimekizumab, binimetinib, bryostatin        1, bucillamine, buparlisib, canakinumab, carfilzomib, cediranib        maleate, cemiplimab, cerdulatinib, chidamide, cilengitide,        cirmtuzumab, clazakizumab, clioquinol, defactinib, defibrotide,        denosumab, diacerein, dinaciclib, durvalumab, duvelisib,        duvortuxizumab, encorafenib, entinostat, entospletinib,        enzastaurin, epacadostat, epratuzumab, eritoran tetrasodium,        eftilagimod alpha, evobrutinib, filgotinib, firategrast,        fontolizumab, forodesine hydrochloride, fostamatinib,        galunisertib, ganetespib, ganitumab, gemtuzumab ozogamicin,        gerilimzumab, glasdegib, glassia, glembatumumab vedotin,        glesatinib, guadecitabine, ibudilast, iguratimod, imexon,        inotuzumab ozogamicin, irofulven, isatuximab, ispinesib,        itacitinib, laquinimod, laromustine, ld-aminopterin, lenvatinib,        lirilumab, lonafarnib, lumiliximab, masitinib, mavrilimumab,        methoxsalen, milatuzumab, mocetinostat, monalizumab,        mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox,        namilumab, navitoclax, neihulizumab, neurovax, niraparib,        obatoclax mesylate, oblimersen sodium, olokizumab, opicinumab,        oprelvekin, otelixizumab, ozanimod, pacritinib, palifermin,        panobinostat, peficitinib, pegsunercept (peg stnf-ri),        penclomedine, perifosine, pevonedistat, pexidartinib,        picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer        acetate, polatuzumab vedotin, ponesimod, pyroxamide, recombinant        il-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept,        sarilumab, secukinumab, selumetinib, sintilimab, siponimod,        siplizumab, sirukumab, sitravatinib, sonidegib, sotrastaurin        acetate, tabalumab, talabostat mesylate, talacotuzumab,        tanespimycin, temsirolimus, tenalisib, terameprocol, thiarabine,        tipifarnib, tirabrutinib, tislelizumab, tivozanib, tregalizumab,        tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib,        urelumab, varlilumab, vatelizumab, veliparib, veltuzumab,        vinorelbine ditartrate, visilizumab, vismodegib, vistusertib,        vosaroxin, and ziv-aflibercept, or any combination thereof.    -   363. The method of any one of paragraphs 352-362, wherein the        one or more immunosuppressive medications comprise natalizumab.    -   364. The method of any one of paragraphs 358-362, wherein the        one or more immunosuppressive medications comprise an antibody        molecule or a fragment thereof.    -   365. The method of paragraph 364, wherein the antibody molecule        or a fragment thereof is a humanized recombinant antibody        molecule or a fragment thereof.    -   366. The method of paragraph 364, wherein the antibody molecule        or a fragment thereof is a humanized recombinant IgG4κ        monoclonal antibody molecule or a fragment thereof.    -   367. The method of paragraph 364, wherein the antibody molecule        or a fragment thereof is produced in murine myeloma cells.    -   368. The method of paragraph 364, wherein the antibody molecule        or a fragment thereof binds an integrin.    -   369. The method of paragraph 368, wherein the integrin is        expressed on surface of a leukocyte.    -   370. The method of paragraph 369, wherein the leukocyte is not a        neutrophil.    -   371. The method of paragraph 364, wherein the antibody molecule        or a fragment thereof binds α4β1 integrin, α4β7 integrin, or        both.    -   372. The method of paragraph 364, wherein the antibody molecule        or a fragment thereof binds α4-subunit of α4β1 integrin, α4β7        integrin, or both.    -   373. The method of paragraph 364, wherein the antibody molecule        or a fragment thereof inhibits α4-mediated adhesion of a        leukocyte to its receptor.    -   374. The method of any one of paragraphs 364-373, wherein the        antibody molecule or a fragment thereof comprises a sequence        that has at least 60%, 70%, 80%, 90%, 95%, or 100% sequence        identity to SEQ ID NO. 3275.    -   375. The method of any one of paragraphs 364-374, wherein the        antibody molecule or a fragment thereof comprises a sequence        that has at least 60%, 70%, 80%, 90%, 95%, or 100% sequence        identity to SEQ ID NO. 3276.    -   376. The method of any one of paragraphs 352-375, wherein the        condition is multiple sclerosis or Crohn's disease.    -   377. The method of paragraph 376, wherein the condition is a        relapsing form of multiple sclerosis.    -   378. The method of paragraph 362, wherein the natalizumab is        administered via intravenous infusion.    -   379. The method of paragraph 362, wherein about 100 mg to about        500 mg of the natalizumab is administered.    -   380. The method of any one of paragraphs 352-379, wherein the        one or more genetic variations are associated with a risk of        developing PML in a polynucleic acid sample from the subject.    -   381. The method of any one of paragraphs 352-380, wherein the        method comprises testing the subject for a genetic        predisposition for PML with a genetic assay.    -   382. The method of paragraph 381, wherein the genetic assay has        a diagnostic yield of at least 20%.    -   383. The method of any one of paragraphs 352-382, wherein the        one or more genetic variations disrupt or modulate a        corresponding gene according to Tables 13-18.    -   384. The method of any one of paragraphs 352-383, wherein the        one or more genetic variations disrupt or modulate a        corresponding gene according to Tables 19-24.    -   385. The method of any one of paragraphs 352-383, wherein the        one or more genetic variations disrupt or modulate a        corresponding gene according to Tables 34-40, and 42.    -   386. The method of any one of paragraphs 352-384, wherein the        one or more genetic variations comprises a first genetic        variation and a second genetic variation, wherein the first        genetic variation disrupts or modulates a corresponding gene        according to Tables 3, 6, 29, 31 and 48, and wherein the second        genetic variation disrupts or modulates a corresponding gene        according to Tables 25A, 25B, and 26.    -   387. The method of any one of paragraphs 352-386, wherein the        one or more genetic variations disrupt or modulate a        corresponding gene selected from the group consisting of Homo        sapiens chromodomain helicase DNA binding protein 7 (CHD7), Homo        sapiens interferon induced with helicase C domain 1 (IFIH1),        Homo sapiens immunoglobulin lambda like polypeptide 1 (IGLL1),        Homo sapiens mitochondrial antiviral signaling protein (MAVS),        Homo sapiens phospholipase C gamma 2 (PLCG2), Homo sapiens        SHANK-associated RH domain interactor (SHARPIN), Homo sapiens        T-cell immune regulator 1, ATPase H+ transporting VO subunit a3        (TCIRG1), and any combination thereof.    -   388. The method of any one of paragraphs 352-387, wherein the        one or more genetic variations comprise chr8:61654298 T>A,        chr2:163136505 C>G, chr22:23917192 G>T, chr20:3846397 C>T,        chr16:81942175 A>G, chr8:145154222 G>A, chr11:67818269 G>A,        chr8:145154824 A>C, chr22:23915745 G>A, chr20:3843027 C>A, or        any combination thereof, wherein the chromosome positions are        defined with respect to UCSC hg19.    -   389. The method of any one of paragraphs 352-388, wherein the        corresponding gene comprises a gene selected from the group        consisting of gene numbers (GNs) GN1-GN765 in Table 3.    -   390. The method of any one of paragraphs 352-388, wherein the        corresponding gene comprises a gene selected from the group        consisting of gene numbers (GNs) GN1-GN490 in Table 6.    -   391. The method of any one of paragraphs 352-388, wherein the        corresponding gene comprises a gene selected from the group        consisting of gene numbers (GNs) GN491-GN492 in Table 29.    -   392. The method of any one of paragraphs 352-388, wherein the        corresponding gene comprises a gene selected from the group        consisting of gene numbers (GNs) GN493-GN762 in Table 31.    -   393. The method of any one of paragraphs 352-388, wherein the        corresponding gene comprises a gene selected from the group        consisting of gene numbers (GNs) GN763-GN765 in Table 48.    -   394. The method of any one of paragraphs 352-388, wherein the        corresponding gene comprises a gene selected from Tables 34-40,        and 42.    -   395. The method of any one of paragraphs 352-389, wherein the        corresponding gene comprises a gene selected from the group        consisting of gene numbers (GNs) GN1-GN241, GN243-GN369, and        GN371-GN490.    -   396. The method of any one of paragraphs 352-395, wherein the        one or more genetic variations are encoded by a sequence with at        least 60% sequence identity to SEQ ID NOs 1-172, 2200-2203 or        SRN1-SRN366, with 100% sequence identity to SEQ ID NOs        1000-1329, 3000-3274, or with at least 80% and less than 100%        sequence identity to GN1-GN765, or complements thereof.    -   397. The method of any one of paragraphs 352-395, wherein the        one or more genetic variations are encoded by a sequence with at        least 60%, at least 70%, at least 80%, at least 90%, at least        95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203        or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs        3000-3274, or with at least 80% and less than 100% sequence        identity to GN491-GN765, or complements thereof.    -   398. The method of any one of paragraphs 352-396, wherein the        one or more genetic variations comprise a genetic variation        encoded by a CNV with at least 60% sequence identity to SEQ ID        NOs 1-172, or complements thereof.    -   399. The method of any one of paragraphs 352-396, wherein the        one or more genetic variations comprise a genetic variation        encoded by a CNV with at least 60%, at least 70%, at least 80%,        at least 90%, at least 95%, or at least 99% sequence identity to        SEQ ID NOs 2200-2203, or complements thereof.    -   400. The method of any one of paragraphs 352-398, wherein the        one or more genetic variations comprise a genetic variation        encoded by a CNV sub-region (SRN) with at least 60% sequence        identity to SRN1-SRN363, or complements thereof.    -   401. The method of any one of paragraphs 352-398, wherein the        one or more genetic variations comprise a genetic variation        encoded by a CNV sub-region (SRN) with at least 60%, at least        70%, at least 80%, at least 90%, at least 95%, or at least 99%        sequence identity to SRN364-SRN366, or complements thereof.    -   402. The method of any one of paragraphs 352-400, wherein the        one or more genetic variations comprise a genetic variation        encoded by a single nucleotide variation (SNV) with a sequence        of any one of SEQ ID NOs: 1000-1329, or complements thereof.    -   403. The method of any one of paragraphs 352-400, wherein the        one or more genetic variations comprise a genetic variation        encoded by a single nucleotide variation (SNV) with a sequence        of any one of SEQ ID NOs: 3000-3274, or complements thereof.    -   404. The method of paragraph 381, wherein the genetic assay        comprises microarray analysis, PCR, sequencing, nucleic acid        hybridization, or any combination thereof.    -   405. The method of any one of paragraphs 352-404, wherein the        method comprises testing the subject with a JCV-antibody test, a        CD62L test, or a CSF IgM oligoclonal bands test.    -   406. The method of paragraph 405, wherein the method comprises        testing the subject with the JCV-antibody test, wherein the        JCV-antibody test does not detect a presence of JCV.    -   407. The method of paragraph 406, wherein the JCV-antibody test        comprises contacting a JCV detection reagent to a biological        sample from the subject.    -   408. The method of paragraph 407, wherein the JCV detection        reagent is selected from the group consisting of an anti-JCV        antibody, a JCV specific primer, and combinations thereof.    -   409. The method of any one of paragraphs 352-408, wherein the        subject is identified as not having one or more genetic        variations that disrupt or modulate a corresponding gene        according to Tables 3, 6, 29, 31 and 48.    -   410. The method of any one of paragraphs 352-408, wherein the        subject is identified as not having one or more genetic        variations that disrupt or modulate a corresponding gene        according to Tables 29 and 31.    -   411. A kit, comprising reagents for assaying a polynucleic acid        sample from a subject in need thereof for the presence of one or        more genetic variations that disrupt or modulate a gene of        GN1-GN765.    -   412. The kit of paragraph 411, comprising reagents for assaying        the polynucleic acid sample from the subject in need thereof for        the presence of the one or more genetic variations that disrupt        or modulate the gene of GN491-GN765.    -   413. A method of treating multiple sclerosis or Crohn's disease        in a subject in need thereof, comprising: administering a        therapeutically effective amount of natalizumab to the subject,        wherein the subject has been tested for a genetic predisposition        for PML with a genetic assay and has been identified as not        having the genetic predisposition for PML, wherein the genetic        assay has a diagnostic yield of at least 20%.    -   414. The method of paragraph 413, wherein the one or more        immunosuppressive medications comprise natalizumab.    -   415. The method of paragraph 413 or 414, wherein the method        further comprises testing the subject with a JCV-antibody test.    -   416. The method of any one of paragraphs 413-415, wherein the        genetic assay tests the subject for the presence of one or more        genetic variations that disrupt or modulate a corresponding gene        according to Tables 3, 6, 29, 31 and 48.    -   417. The method of any one of paragraphs 413-415, wherein the        genetic assay tests the subject for the presence of one or more        genetic variations that disrupt or modulate a corresponding gene        according to Tables 29 and 31.    -   418. A method of identifying a subject as not having a risk of        developing PML, comprising:        -   (a) analyzing a polynucleic acid sample from the subject for            one or more genetic variations that disrupt or modulate a            corresponding gene according to Tables 3, 6, 29, 31 and 48,            wherein a genetic variation of the one or more genetic            variations that disrupt or modulate a corresponding gene            according to Tables 3, 6, 29, 31 and 48 is not present in            the polynucleic acid sample; and        -   (b) identifying the subject as not having a risk of            developing PML.    -   419. The method of any one of paragraphs 357-418, wherein the        diseased cohort of subjects, the non-diseased cohort of        subjects, or both cohorts of subjects are ethnically matched.    -   420. The method of any one of paragraphs 364-419, wherein the        antibody molecule or fragment thereof comprises at least one        antibody heavy chain, or an α4-binding fragment thereof,        comprising non-human CDRs at positions 31-35 (CDR1), 50-65        (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4        antibody and having non-human residues at framework positions        27-30 (Kabat numbering), wherein said positions 27-30 have the        amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30.    -   421. The method of paragraph 420, wherein the antibody molecule        or fragment thereof comprises at least one antibody light chain,        or an α4-binding fragment thereof, comprising: a light chain        (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3277        (KTSQDINKYMA), a LC CDR2 with an amino acid sequence of SEQ ID        NO.: 3278 (YTSALQP), and a LC CDR3 with an amino acid sequence        of SEQ ID NO.: 3279 (LQYDNLWT).    -   422. The method of paragraph 420, wherein the antibody molecule        or fragment thereof comprises at least one antibody light chain,        or an α4-binding fragment thereof, comprising: a light chain        (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3280        (QASQDIIKYLN), a LC CDR2 with an amino acid sequence of SEQ ID        NO.: 3281 (EASNLQA), and a LC CDR3 with an amino acid sequence        of SEQ ID NO.: 3282 (QQYQSLPYT).    -   423. The method of paragraph 420, wherein the antibody molecule        or fragment thereof comprises at least one antibody light chain,        or an α4-binding fragment thereof, comprising: a light chain        (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3283        (KASQSVTNDVA), a LC CDR2 with an amino acid sequence of SEQ ID        NO.: 3284 (YASNRYT), and a LC CDR3 with an amino acid sequence        of SEQ ID NO.: 3285 (QQDYSSPYT).    -   424. The method of any one of paragraphs 420-423, wherein the        antibody molecule or fragment thereof comprises at least one        antibody heavy chain, or an α4-binding fragment thereof,        comprising: a heavy chain (HC) CDR1 with an amino acid sequence        of SEQ ID NO.: 3286 (DTYIH), a HC CDR2 with an amino acid        sequence of SEQ ID NO.: 3287 (RIDPANGYTKYDPKFQG), and a HC CDR3        with an amino acid sequence of SEQ ID NO.: 3288        (EGYYGNYGVYAMDY).    -   425. The method of any one of paragraphs 420423, wherein the        antibody molecule or fragment thereof comprises at least one        antibody heavy chain, or an α4-binding fragment thereof,        comprising: a heavy chain (HC) CDR1 with an amino acid sequence        of SEQ ID NO.: 3289 (DTYMH), a HC CDR2 with an amino acid        sequence of SEQ ID NO.: 3290 (RIDPASGDTKYDPKFQV), and a HC CDR3        with an amino acid sequence of SEQ ID NO.: 3291 (DGMWVSTGYALDF).    -   426. The method of any one of paragraphs 420-425, wherein the        antibody molecule or fragment thereof comprises a humanized        heavy chain, or an α4-binding fragment thereof, comprising: a        variable heavy chain region selected from the group consisting        of: SEQ ID NO.: 3292        (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTVSGFNIKDTYMHWVRQPPGR        GLEWIGRIDPASGDTKYDPKFQVKATITADTSSNQFSLRLSSVTAADTAVYYCADGMWVSTGY        ALDFWGQGTTVTVSSGES), SEQ ID NO.: 3293        (QVQLQESGPGLVRPSQTLSLTCTVSGFNIKDTYMHWVRQPPGRGLEWIGRIDPASGDTKYDPKF        QVRVTMLVDTSSNQFSLRLSSVTSEDTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES),        SEQ ID NO.: 3294        (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTVSGFNIKDTYMHWVKQRPGR        GLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFSLRLSSVTAADTAVYYCADGMWVSTGY        ALDFWGQGTTVTVSSGES), SEQ ID NO.: 3295        (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTASGFNIKDTYMHWVRQPPGR        GLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFSLRLSSVTAADTAVYYCADGMWVSTGY        ALDFWGQGTTVTVSSGES), and SEQ ID NO.: 3296        (QVQLVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQRLEWMGRIDPANGYTKYDP        KFQGRVTITADTSASTAYMELSSLRSEDTAVYYCAREGYYGNYGVYAMDYWGQGTLVTVSS).    -   427. The method of any one of paragraphs 420-426, wherein the        antibody molecule or fragment thereof comprises a humanized        light chain, or an α4-binding fragment thereof, comprising a        variable light chain region selected from the group consisting        of: SEQ ID NO.: 3297        (MGWSCIILFLVATATGVHSDIQLTQSPSSLSASVGDRVTITCKASQSVTNDVAWYQQKPGKAPK        LLIYYASNRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQDYSSPYTFGQGTKVEIKRK),        SEQ ID NO.: 3298        (MGWSCIILFLVATATGVHSSIVMTQSPSSLSASVGDRVTITCKASQSVTNDVAWYQQKPGKAPK        LLIYYASNRYTGVPDRFSGSGYGTDFTFTISSLQPEDIATYYCQQDYSSPYTFGQGTKVEIKRK),        SEQ ID NO.: 3299        (MGWSCIILFLVATATGVHSDIQMTQSPSSLSASVGDRVTITCKASQSVTNDVAWYQQKPGKAP        KLLIYYASNRYTGVPDRFSGSGYGTDFTFTISSLQPEDIATYYCQQDYSSPYTFGQGTKVEIKRK),        and SEQ ID NO.: 3300        (DIQMTQSPSSLSASVGDRVTITCKTSQDINKYMAWYQQTPGKAPRLLIHYTSALQPGIPSRFSGS        GSGRDYTFTISSLQPEDIATYYCLQYDNLWTFGQGTKVEIKRTV).    -   428. A method of treating a condition in a subject in need of        natalizumab therapy, comprising: administering a therapeutically        effective amount of natalizumab to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), wherein the subject's decreased        risk is associated with an absence of one or more genetic        variations in the subject, wherein the subject has been tested        for a presence of the one or more genetic variations with a        genetic assay and has been identified as not having the one or        more genetic variations selected from Table 43.    -   429. A method of treating a condition in a subject in need of        natalizumab therapy, comprising: administering a therapeutically        effective amount of natalizumab to the subject, wherein the        subject has a decreased risk of progressive multifocal        leukoencephalopathy (PML) due to an infection of the brain by        John Cunningham virus (JCV), wherein the subject's decreased        risk is associated with a presence of one or more genetic        variations in the subject, wherein the subject has been tested        for a presence of the one or more genetic variations with a        genetic assay and has been identified as having the one or more        genetic variations selected from Table 44.

What is claimed is:
 1. A method of treating a condition in a subject inneed of immunosuppressive therapy comprising: administering atherapeutically effective amount of an immunosuppressive agent to thesubject, wherein the subject has a decreased risk of progressivemultifocal leukoencephalopathy (PML) due to an infection of the brain byJohn Cunningham virus (JCV), wherein the subject's decreased risk isassociated with the absence of one or more genetic variations in thesubject, wherein the subject has been tested for a presence of the oneor more genetic variations with a genetic assay and has been identifiedas not having the one or more genetic variations; wherein the one ormore genetic variations disrupts or modulates a C8B gene, a FCN2 gene,or a LY9 gene.
 2. The method of claim 1, wherein the condition is lupus.3. The method of claim 2, wherein the condition is systemic lupuserythematosus.
 4. The method of claim 1, wherein the immunosuppressiveagent is belimumab, teriflunomide, fingolimod, rituximab, daclizumab,obinutuzumab, ocrelizumab, ofatumumab, siponimod or any combinationthereof.
 5. The method of claim 4, wherein the immunosuppressive agentis belimumab.
 6. The method of claim 1, wherein the one or more geneticvariations comprises chr1:57409459 C>A, chr9:137779251 G>A, orchr1:160769595 AG>A; wherein chromosome positions of the one or moregenetic variations are defined with respect to UCSC hg19.
 7. The methodof claim 1, wherein the one or more genetic variations disrupts ormodulates a C8B gene.
 8. The method of claim 7, wherein the one or moregenetic variations comprises chr1:57409459 C>A, wherein chromosomepositions of the one or more genetic variations are defined with respectto UCSC hg19.
 9. The method of claim 1, wherein the one or more geneticvariations disrupts or modulates a FCN2 gene.
 10. The method of claim 9,wherein the one or more genetic variations comprises chr9:137779251 G>A,wherein chromosome positions of the one or more genetic variations aredefined with respect to UCSC hg19.
 11. The method of claim 1, whereinthe one or more genetic variations disrupts or modulates a LY9 gene. 12.The method of claim 11, wherein the one or more genetic variationscomprises chr1:160769595 AG>A, wherein chromosome positions of the oneor more genetic variations are defined with respect to UCSC hg19. 13.The method of claim 1, wherein (i) the condition is lupus or systemiclupus erythematosus, (ii) the immunosuppressive agent is belimumab, and(iii) the one or more genetic variations comprises chr1:57409459 C>A,chr9:137779251 G>A, or chr1:160769595 AG>A; wherein chromosome positionsof the one or more genetic variations are defined with respect to UCSChg19.
 14. The method of claim 1, wherein the subject has been testedwith a genetic assay for a genetic variation that disrupts or modulatesa STXBP2 gene and wherein the subject has been identified as not havinga genetic variation that disrupts or modulates a STXBP2 gene.
 15. Themethod of claim 14, wherein the genetic variation that disrupts ormodulates a STXBP2 gene comprises chr19:7712287 G>C; wherein chromosomepositions of the one or more genetic variations are defined with respectto UCSC hg19.
 16. The method of claim 1, wherein the subject has beentested with a genetic assay for at least two of: (i) a genetic variationthat disrupts or modulates a STXBP2 gene, (ii) a genetic variation thatdisrupts or modulates a C8B gene, (iii) a genetic variation thatdisrupts or modulates a FCN2 gene, and (iv) a genetic variation thatdisrupts or modulates a LY9 gene; and wherein the subject has beenidentified as not having at least two of (i)-(iv).
 17. The method ofclaim 1, wherein the subject has been tested with a genetic assay for apresence of a genetic variation that disrupts or modulates a C8B gene, agenetic variation that disrupts or modulates a FCN2 gene, and a geneticvariation that disrupts or modulates a LY9 gene, and wherein the subjecthas been identified as: (i) not having a genetic variation that disruptsor modulates a C8B gene (ii) not having a genetic variation thatdisrupts or modulates a FCN2 gene; and (iii) not having a geneticvariation that disrupts or modulates a LY9 gene.
 18. The method of claim1, wherein the subject has been tested with a genetic assay for apresence of a genetic variation that disrupts or modulates a STXBP2gene, a C8B gene, a genetic variation that disrupts or modulates a FCN2gene, and a genetic variation that disrupts or modulates a LY9 gene, andwherein the subject has been identified as: (i) not having a geneticvariation that disrupts or modulates a C8B gene, (ii) not having agenetic variation that disrupts or modulates a FCN2 gene, (iii) nothaving a genetic variation that disrupts or modulates a LY9 gene, and(iv) not having a genetic variation that disrupts or modulates a STXBP2gene.
 19. The method of claim 1, wherein the one or more geneticvariations comprise an SNV in a gene selected from the group consistingof C8B, FCN2 and LY9.
 20. The method of claim 1, wherein the subject hasbeen identified as not having one or more other genetic variations thatdisrupt or modulate a corresponding gene according to Tables 1, 3, 6-10,19-24, 28A, 29, 31, 34-36, 40, 42, 47 and
 48. 21. The method of claim 1,wherein the subject has been tested with a JCV-antibody test, a CD62Ltest, or a CSF IgM oligoclonal bands test.
 22. The method of claim 1,wherein the method further comprises testing the subject for thepresence of the one or more genetic variations with the genetic assayprior to the administering.
 23. The method of claim 22, wherein thegenetic assay comprises microarray analysis, PCR, sequencing, nucleicacid hybridization, or any combination thereof.
 24. The method of claim22, wherein prior to testing the subject for the presence of the one ormore genetic variations with the genetic assay the method furthercomprises obtaining biological samples from subjects with PML and (a)confirming each biological sample is not a duplicate of any otherbiological sample based on nucleic acid information of the biologicalsamples or (b) determining a sex genotype for each biological samplebased on nucleic acid information of the biological samples, andconfirming the sex genotype of each biological sample is the same as asex phenotype of the subject with PML from which the biological samplewas obtained.
 25. A method of assessing a risk in a subject with acondition for developing progressive multifocal leukoencephalopathy(PML) in response to an immunosuppressive agent for treating animmunosuppressive condition of the subject, comprising: (a) testing forthe presence of one or more genetic variations in a sample obtained fromthe subject, wherein testing comprises testing for the presence of theone or more genetic variations with a genetic assay; and (b)(1)correlating the presence of one or more genetic variations tested in thesample with an increased risk in the subject for developing PML inresponse to an immunosuppressive agent for treating an immunosuppressivecondition of the subject, or (b)(2) identifying the subject as havingone or more genetic variations based on the testing and as having anincreased risk for developing PML in response to an immunosuppressiveagent for treating an immunosuppressive condition of the subject;wherein the increased risk for developing PML in response to theimmunosuppressive agent for treating an immunosuppressive condition ofthe subject is associated with the presence of the one or more geneticvariations tested in the subject, wherein the one or more geneticvariations disrupts or modulates a C8B gene, a FCN2 gene, or a LY9 gene.26. The method of claim 25, wherein the condition is lupus or systemiclupus erythematosus, and the immunosuppressive agent is belimumab. 27.The method of claim 25, wherein the one or more genetic variationscomprises chr1:57409459 C>A, chr9:137779251 G>A, or chr1:160769595 AG>A;wherein chromosome positions of the one or more genetic variations aredefined with respect to UCSC hg19.
 28. A method of determining whetherto administer an immunosuppressive agent to a subject with a conditionin need of an immunosuppressive agent comprising: (a) testing for thepresence of one or more genetic variations in a sample obtained from thesubject, wherein testing comprises testing for the presence of the oneor more genetic variations with a genetic assay; and (b) excluding thesubject from an immunosuppressive medication based on the presence ofone or more genetic variations in the subject; wherein an increased riskfor developing PML in response to the immunosuppressive agent isassociated with the presence of one or more genetic variations in thesubject, wherein the one or more genetic variations disrupts ormodulates a C8B gene, a FCN2 gene, or a LY9 gene.
 29. The method ofclaim 28, wherein the condition is lupus or systemic lupuserythematosus, and the immunosuppressive agent is belimumab.
 30. Themethod of claim 28, wherein the one or more genetic variations compriseschr1:57409459 C>A, chr9:137779251 G>A, or chr1:160769595 AG>A; whereinchromosome positions of the one or more genetic variations are definedwith respect to UCSC hg19.